Compounds for the treatment of alzheimer&#39;s disease

ABSTRACT

The invention relates to compounds of formula (I). Useful in treating Alzheimer&#39;s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer&#39;s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 60/414,287, filed Sep. 27, 2002, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to substituted amino alcohols and to suchcompounds that are useful in the treatment of Alzheimer's disease andrelated diseases. More specifically, it relates to such compounds thatare capable of inhibiting beta-secretase, an enzyme that cleaves amyloidprecursor protein to produce amyloid beta peptide (A beta), a majorcomponent of the amyloid plaques found in the brains of Alzheimer'ssufferers.

2. Background of the Invention

Alzheimer's disease (AD) is a progressive degenerative disease of thebrain primarily associated with aging. Clinical presentation of AD ischaracterized by loss of memory, cognition, reasoning, judgment, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWA-D), and other neurodegenerative disorders.Beta-amyloid is a defining feature of AD, now believed to be a causativeprecursor or factor in the development of disease. Deposition of A betain areas of the brain responsible for cognitive activities is a majorfactor in the development of AD. Beta-amyloid plaques are predominantlycomposed of amyloid beta peptide (A beta, also sometimes designatedbetaA4). A beta peptide is derived by proteolysis of the amyloidprecursor protein (APP) and is comprised of 39-42 amino acids. Severalproteases called secretases are involved in the processing of APP.

Cleavage of APP at the N-terminus of the A beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

An aspartyl protease has been identified as the enzyme responsible forprocessing of APP at the beta-secretase cleavage site. Thebeta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sinha et al., 1999,Nature 402:537-554 (p 501) and published PCT application WO00/17369.

Several lines of evidence indicate that progressive cerebral depositionof beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

It has been proposed that A beta peptide accumulates as a result of APPprocessing by beta-secretase, thus inhibition of this enzyme's activityis desirable for the treatment of AD. In vivo processing of APP at thebeta-secretase cleavage site is thought to be a rate-limiting step in Abeta production, and is thus a therapeutic target for the treatment ofAD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.

BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that over express APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

At present there are no effective treatments for halting, preventing, orreversing the progression of Alzheimer's disease. Therefore, there is anurgent need for pharmaceutical agents capable of slowing the progressionof Alzheimer's disease and/or preventing it in the first place.

Compounds that are effective inhibitors of beta-secretase, that inhibitbeta-secretase-mediated cleavage of APP, that are effective inhibitorsof A beta production, and/or are effective to reduce amyloid betadeposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

The invention encompasses the compounds of formula (I) shown below,pharmaceutical compositions containing the compounds and methodsemploying such compounds or compositions in the treatment of Alzheimer'sdisease and more specifically compounds that are capable of inhibitingbeta-secretase, an enzyme that cleaves amyloid precursor protein toproduce A-beta peptide, a major component of the amyloid plaques foundin the brains of Alzheimer's sufferers.

In one aspect, the invention provides compounds of the formula I:

and pharmaceutically acceptable salts or esters thereof, wherein R₂₀ isH, C₁₋₆ alkyl or alkenyl, C₁₋₆ haloalkyl or C₄₋₇ cycloalkyl;

-   R₁ is —(CH₂)₁₋₂—S(O)₀₋₂- (C₀-C₆ alkyl), or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—,        —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with 1, 2, or 3 groups independently selected from        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or        dialkylamino, or    -   aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆        alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring        portions of each are optionally substituted with 1, 2, 3, or 4        groups independently selected from halogen, —OH, —SH, —C≡N,        —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄)        alkyl, —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino,        —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or        -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups            which are independently selected from halogen, or        -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3            groups independently selected from halogen, —OH, —SH, —C≡N,            —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or            dialkylamino, or        -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups            independently selected from halogen, —OH, —SH, —C≡N, —CF₃,            —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃            alkyl, or        -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally            substituted with 1, 2, or 3 groups independently selected            from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino,            C₁-C₆ alkyl and mono- or dialkylamino; and the heterocyclyl            group is optionally further substituted with oxo;-   R and R′ independently are hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkylaryl    or C₁-C₁₀ alkylheteroaryl;-   R_(C) is hydrogen, —(CR₂₄₅R₂₅₀)₀₋₄-aryl, —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl, —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocyclyl, —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocyclyl,    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heterocyclyl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-aryl, —[C(R₂₅₅)    (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂; —CH(aryl)₂, —CH(heteroaryl)₂,    —CH(heterocyclyl)₂, —CH(aryl)(heteroaryl),    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl,    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₆-heteroaryl, —CH(-aryl or    -heteroaryl)-CO—O(C₁-C₄ alkyl), —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂,    (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,    —(CH₂)₀₋₆—C(═NR₂₃₅)(NR₂₃₅R₂₄₀), or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from the group consisting of R₂₀₅,        —OC═ONR₂₃₅R₂₄₀′—S(═O)₀₋₂(C₁-C₆ alkyl), —SH, —NR₂₃₅C═ONR₂₃₅R₂₄₀,        —C═ONR₂₃₅R₂₄₀, and —S(═O)₂NR₂₃₅R₂₄₀, or    -   —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is        optionally substituted with 1, 2, or 3 groups independently        selected from the group consisting of R₂₀₅, —CO₂H, and        —CO₂—(C₁-C₄ alkyl), or    -   cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl,        heteroaryl, or heterocyclyl wherein one, two or three carbons of        the cyclopentyl, cyclohexyl, or cycloheptyl is optionally        replaced with a heteroatom independently selected from NH,        NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentyl, cyclohexyl,        or cycloheptyl group can be optionally substituted with one or        two groups that are independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or        —SO₂—(C₁-C₄ alkyl), or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionally        substituted with 1, 2, or 3 R₂₀₅ groups, wherein    -   each aryl and heteroaryl is optionally substituted with 1, 2, or        3 R₂₀₀, and wherein each heterocyclyl is optionally substituted        with 1, 2, 3, or 4 R₂₁₀;-   R₂₀₀ at each occurrence is independently selected from —OH, —NO₂,    halogen, —CO₂H, C—N, —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—CO—(C₁-C₁₂    alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂    alkynyl), —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—CO-aryl,    —(CH₂)₀₋₄—CO-heteroaryl, —(CH₂)₀₋₄—CO-heterocyclyl,    —(CH₂)₀₋₄—CO—O—R₂₁₅, —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—SO—(C₁-C₆    alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂—(C₃-C₇    cycloalkyl), —(CH₂)₀₋₄—N(H or R₂₁₃)—CO—O—R₂₁₅, —(CH₂)₀₋₄—N(H or    R₂₁₅)—CO—N(R₂₁₅)₂, —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—N(—H or    R₂₁₅)—CO—R₂₂₀, —(CH₂)₀₋₄—NR₂₂₀R₂₂₅—, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),    —(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂, —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂,    —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—O—(R₂₁₅),    —(CH₂)₀₋₄—O—(R₂₁₅)—COOH, —(CH₂)₀₋₄—S—(R₂₁₅), —(CH₂)₀₋₄—O—(C₁-C₆    alkyl optionally substituted with 1, 2, 3, or 5-F), C₃-C₇    cycloalkyl, —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀, —(CH₂)₀₋₄—C₃-C₇    cycloalkyl, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups,        or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionally        substituted with 1 or 2 R₂₀₅ groups, wherein    -   the aryl and heteroaryl groups at each occurrence are optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀, or        -   C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are            independently R₂₀₅ or R₂₁₀, and wherein    -   the heterocyclyl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₁₀;-   R₂₀₅ at each occurrence is independently selected from C₁-C₆ alkyl,    halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂,    NH(C₁-C₆ alkyl) or N—(C₁-C₆ alkyl) (C₁-C₆ alkyl);-   R₂₁₀ at each occurrence is independently selected from halogen,    C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅, OH, C≡N, —CO—(C₁-C₄    alkyl), SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂—(C₁-C₄ alkyl), ═O, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₇ cycloalkyl,        each of which is optionally substituted with 1, 2, or 3 R₂₀₅        groups;-   R₂₁₅ at each occurrence is independently selected from C₁-C₆ alkyl,    —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocyclyl), wherein    -   the aryl group at each occurrence is optionally substituted with        1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀, and        wherein    -   the heterocyclyl and heteroaryl groups at each occurrence are        optionally substituted with 1, 2, or 3 R₂₁₀;-   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from —H,    —C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(c₃-C₇ cycloalkyl), —(C₁-C₆    alkyl)-O—(C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl    chain with one double bond and one triple bond, -aryl, -heteroaryl,    and -heterocyclyl, or    -   —C₁-C₁₀ alkyl optionally substituted with —OH, —NH₂ or halogen,        wherein    -   the aryl, heterocyclyl and heteroaryl groups at each occurrence        are optionally substituted with 1, 2, or 3 R₂₇₀ groups-   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆    alkyl;-   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from —H,    C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄ alkylheteroaryl, C₁-C₄    hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(CH₂)₀₋₄—C₃-C₇    cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and phenyl; or-   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are    attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,    where one carbon atom is optionally replaced by a heteroatom    selected from —O—, —S—, —SO₂—, and —NR₂₂₀—;-   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from —H,    —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), —(C₁-C₄ alkyl)-aryl, —(C₁-C₄    alkyl)-heteroaryl, —(C₁-C₄ alkyl)-heterocyclyl, -aryl, -heteroaryl,    -heterocyclyl, —(CH₂)₁₋₄—R₂₆₅-(CH₂)₀₋₄-aryl,    —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl,    —(CH₂)₁₋₄—R₂₆₅-(CH₂)₀₋₄-heterocyclyl, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇        cycloalkyl, each of which is optionally substituted with 1, 2,        or 3 R₂₀₅ groups, wherein    -   each aryl or phenyl is optionally substituted with 1, 2, or 3        groups that are independently R₂₀5, R₂₁₀, or        -   C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are            independently R₂₀₅ or R₂₁₀, and wherein    -   each heterocyclyl is optionally substituted with 1, 2, 3, or 4        R₂₁₀;-   R₂₆₅ at each occurrence is independently —O—, —S— or —N(C₁-C₆    alkyl)-;-   R₂₇₀ at each occurrence is independently R₂₀₅, halogen C₁-C₆ alkoxy,    C₁-C₆ haloalkoxy, NR₂₃₅R₂₄₀, —OH, —C_N, —CO—(C₁-C₄ alkyl),    —SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂—(C₁-C₄ alkyl), ═O, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇        cycloalkyl, each of which is optionally substituted with 1, 2,        or 3 R₂₀₅ groups;-   R_(N) is R′₁₀₀, —C(═O)—NR₁₀₀—R′₁₀₀, —C(═O)O—R′₁₀₀, —SO₂R′₁₀₀,    —(CRR′)₁₋₆R′₁₀₀, —C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O)—(CRR′)₁₋₆—O—R′₁₀₀,    —C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, —C(═O)—(CRR′)₁₋₆—C(═O)—R₁₀₀,    —C(═O)—(CRR′)₁₋₆—SO₂—R₁₀₀, —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀, or    -   wherein-   R₄ is selected from the group consisting of H; NH₂;    —NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; C₁-C₄ alkyl-NHC(O)R₅;    —(CH₂)₀₋₄R₈; —O—C₁-C₄ alkanoyl; OH; C₆-C₁₀ aryloxy optionally    substituted with 1, 2, or 3 groups that are independently halogen,    C₁-C₄ alkyl, —CO₂H, —C(O)—C₁-C₄ alkoxy, or C₁-C₄ alkoxy; C₁-C₆    alkoxy; aryl C₁-C₄ alkoxy; —NR₅₀CO₂R₅₁; —C₁-C₄ alkyl-NR₅₀CO₂R₅₁;    —C≡N; —CF₃; —CF₂—CF₃; —C≡CH; —CH₂—CH═CH₂; —(CH₂)₁₋₄—R₄₋₁;    —(CH₂)₁₋₄—NH—R₄₋₁; —O—(CH₂)_(n6)—R₄₋₁; —S—(CH₂)_(n6)—R₄₋₁;    —(CH₂)₀₋₄—NHC(O)—(CH₂)₀₋₆—R₅₂; —(CH₂)₀₋₄—R₅₃—(CH₂)₀₋₄—R₅₄;    -   wherein        -   n₆ is 0, 1, 2, or 3;        -   n₇ is 0, 1, 2, or 3;    -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈        alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆        alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;    -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆        cycloalkyl;    -   R₄₋₄ is alkyl, arylalkyl, alkanoyl, or arylalkanoyl;    -   R₄₋₆ is —H or C₁-C₆ alkyl;    -   R₅ is selected from the group consisting of C₃-C₇ cycloalkyl;        C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that        are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆        heterocycloalkyl, C₅-C₆ heteroaryl, C₆-C₁₀ aryl, C₃-C₇        cycloalkyl C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H,        —CONR₆R₇, —CO₂—C₁-C₄ alkyl, C₆-C₁₀ aryloxy; heteroaryl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄        haloalkyl, or OH; heterocycloalkyl optionally substituted with        1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, or C₂-C₄ alkanoyl; aryl optionally substituted        with 1, 2, 3, or 4 groups that are independently halogen, OH,        C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R₇;        wherein        -   R₆ and R₇ are independently selected from the group            consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl,            —SO₂—C₁-C₄ alkyl, phenyl C₁-C₄ alkyl;    -   R₈ is selected from the group consisting of —SO₂-heteroaryl,        —SO₂-aryl, —SO₂-heterocycloalkyl, —SO₂—C₁-C₁₀ alkyl, —C(O)NHR₉,        heterocycloalkyl, —S—C₁-C₆ alkyl, —S—C₂-C₄ alkanoyl, wherein        -   R₉ is aryl C₁-C₄ alkyl, C₁-C₆ alkyl, or H;    -    R₅₀ is H or C₁-C₆ alkyl;    -   R₅₁ is selected from the group consisting of aryl C₁-C₄ alkyl;        C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that        are independently halogen, cyano, heteroaryl, —NR₆R₇,        —C(O)NR₆R₇, C₃-C₇ cycloalkyl, or —C₁-C₄ alkoxy; heterocycloalkyl        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, aryl C₁-C₄        alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl        optionally substituted with 1, 2, or 3 groups that are        independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂,        NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); heteroarylalkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆        alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); aryl; heterocycloalkyl;        C₃-C₈ cycloalkyl; and cycloalkylalkyl; wherein the aryl;        heterocycloalkyl, C₃-C₈ cycloalkyl, and cycloalkylalkyl groups        are optionally substituted with 1, 2, 3, 4 or 5 groups that are        independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆        alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆        thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy;    -   R₅₂ is heterocycloalkyl, heteroaryl, aryl, cycloalkyl,        —S(O)₀₋₂—C₁-C₆ alkyl, CO₂H, —C(O)NH₂, —C(O)NH(alkyl)        —C(O)N(alkyl)(alkyl), —CO₂-alkyl, —NHS(O)₀₋₂—C₁-C₆ alkyl,        —N(alkyl)S(O)₀₋₂—C₁-C₆ alkyl, —S(O)₀₋₂-heteroaryl,        —S(O)₀₋₂-aryl, —NH(arylalkyl), —N(alkyl)(arylalkyl), thioalkoxy,        or alkoxy, each of which is optionally substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, alkoxy, thioalkoxy,        halogen, haloalkyl, haloalkoxy, alkanoyl, NO₂, CN,        alkoxycarbonyl, or aminocarbonyl;    -   R₅₃ is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O)₀₋₂—,        —N(alkyl)-S(O)₀₋₂—S(O)₀₋₂—NH—, —S(O)₀₋₂- N(alkyl)-, —NH—C(S)—,        or —N(alkyl)-C(S)—;    -   R₅₄ is heteroaryl, aryl, arylalkyl, heterocycloalkyl, CO₂H,        —CO₂-alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —C(O)NH₂,        C₁-C₈ alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH₂, NH(alkyl),        N(alkyl) (alkyl), or —C₁-C₆ alkyl-CO₂—C₁-C₆ alkyl, each of which        is optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently alkyl, alkoxy, CO₂H, —CO₂-alkyl, thioalkoxy,        halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO₂, CN,        alkoxycarbonyl, or aminocarbonyl;-   X′ is selected from the group consisting of —C₁-C₆ alkylidenyl    optionally optionally substituted with 1, 2, or 3 methyl groups; and    —NR₄₋₆—; or    -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein        -   n₁₀ is 1, 2, 3, or 4;-   Z is selected from the group consisting of a bond; SO₂; SO; S; and    C(O);-   Y is selected from the group consisting of H; C₁-C₄ haloalkyl; C₅-C₆    heterocycloalkyl; C₆-C₁₀ aryl; OH; —N(Y₁) (Y₂); C₁-C₁₀ alkyl    optionally substituted with 1 thru 3 substituents which can be the    same or different and are selected from the group consisting of    halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈    cycloalkyl optionally substituted with 1, 2, or 3 groups    independently selected from C₁-C₃ alkyl, and halogen; alkoxy; aryl    optionally substituted with halogen, alkyl, alkoxy, CN or NO₂;    arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or    NO₂; wherein    -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl        optionally substituted with 1, 2, or 3 substituents selected        from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈        cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;        —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄        alkyl; or    -   Y₁, Y₂ and the nitrogen to which they are attached form a ring        selected from the group consisting of piperazinyl, piperidinyl,        morpholinyl, and pyrolidinyl, wherein each ring is optionally        substituted with 1, 2, 3, or 4 groups that are independently        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen;-   R₁₀₀ and R′₁₀₀ independently represent aryl, heteroaryl,    -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl,    -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,    -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,    -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl,    —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl,    —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heterocyclyl or    —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of    each are optionally substituted with 1, 2, or 3 groups independently    selected from    -   —OR, —NO₂, halogen, —C≡N, —OCF₃, —CF₃,        —(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,        (CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),        —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),        —(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl),        —(CH₂)₀₋₄—R₁₁₀—(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₀₀,        —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,        —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,        —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),        —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),        —(CH₂)₀₋₄—N(R₁₁₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,        —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,        —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—CO—(C₁-C₆        alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,        —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),        —(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),        —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄-C₃-C₇ cycloalkyl,        (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl, or-   R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅    groups, or-   R₁₀₀ is —(C₁-C₆ alkyl)-O—C₁-C₆ alkyl) or —(C₁-C₆ alkyl)-S—(C₁-C₆    alkyl), each of which is optionally substituted with 1, 2, or 3 R₁₁₅    groups, or-   R₁₀₀ is C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅    groups;-   W is —(CH₂)₀₋₄—, —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—;-   R₁₀₂ and R₁₀₂′ independently are hydrogen, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups that        are independently halogen, aryl or —R₁₁₀;-   R₁₀₅ and R′₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇    cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆    alkyl)-O—(C₁-C₃ alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl    chain with one double bond and one triple bond, or    -   C₁-C₆ alkyl optionally substituted with —OH or —NH₂; or,    -   C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, or-   R₁₀₅ and R′₁₀₅ together with the atom to which they are attached    form a 3 to 7 membered carbocylic ring, where one member is    optionally a heteratom selected from —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the    ring being optionally substituted with 1, 2 or three R₁₄₀ groups;-   R₁₁₅ at each occurrence is independently halogen, —OH, —CO₂R₁₀₂,    —C₁-C₆ thioalkoxy, —CO₂-phenyl, —NR₁₀₅R′₁₃₅, —SO₂—(C₁-C₈ alkyl),    —C(═O)R₁₈₀, R₁₈₀, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅′—NH—CO—(C₁-C₆    alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,    —O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or    dialkylamino, —O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆    alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy;-   R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or    —(CH₂)₀₋₂-(heterocyclyl);-   R₁₄₀ is heterocyclyl optionally substituted with 1, 2, 3, or 4    groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆) alkylamino,    di(C₁-C₆) alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,    C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,    mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,    and ═O;-   R₁₅₀ is hydrogen, C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(c₃-C₇    cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one    double bond and one triple bond, —R₁₁₀, —R₁₂₀, or    -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups        independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and        halogen;-   R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one    triple bond, —R₁₁₀, —R₁₂₀, or    -   C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groups        independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and        halogen;-   R₁₈₀ is selected from morpholinyl, thiomorpholinyl, piperazinyl,    piperidinyl, homomorpholinyl, homothiomorpholinyl,    homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,    pyrrolinyl and pyrrolidinyl, each of which is optionally substituted    with 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl,    C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆)    alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,    mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₃-C₆)alkyl,    and ═O;-   R₁₁₀ is aryl optionally substituted with 1 or 2 R₁₂₅ groups;-   R₁₂₅ at each occurrence is independently halogen, amino, mono- or    dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆    alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or    —CO—N(C₁-C₆ alkyl)₂, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is        optionally substituted with 1, 2, or 3 groups that are        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C—N, —CF₃, C₁-C₃ alkoxy, amino, and mono- and dialkylamino, or    -   C₁-C₆ alkoxy optionally substituted with one, two or three of        halogen;-   R₁₂₀ is heteroaryl, which is optionally substituted with 1 or 2 R₁₂₅    groups; and-   R₁₃₀ is heterocyclyl optionally substituted with 1 or 2 R₁₂₅ groups;    and-   R₂ is selected from the group consisting of H; C₁-C₆ alkyl,    optionally substituted with 1, 2, or 3 substituents that are    independently selected from the group consisting of C₁-C₃ alkyl,    halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b);    wherein    -   R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl;    -   —(CH₂)₀₋₄-aryl; —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆        alkynyl; —CONR_(N-2)R_(N-3); —SO₂NR_(N-2)R_(N-3); —CO₂H; and        —CO₂—(C₁-C₄ alkyl);-   R₃ is selected from the group consisting of H; C₁-C₆ alkyl,    optionally substituted with 1, 2, or 3 substituents independently    selected from the group consisting of c₁-C₃ alkyl, halogen, —OH,    —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b); —(CH₂)₀₋₄-aryl;    —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl;    —CO—NR_(n-2)R_(n-3); —SO₂—NR_(n-2)R_(n-3); —CO₂H; and —CO—O—(C₁-C₄    alkyl);    -   wherein        -   R_(N-2) and R_(N-3) at each occurrence are independently            selected from the group consisting of —C₁-C₈ alkyl            optionally substituted with 1, 2, or 3 groups independently            selected from the group consisting of —OH, —NH₂, phenyl and            halogen; —C₃-C₈ cycloalkyl; —(C₁-C₂ alkyl)-(C₃-C₈            cycloalkyl); —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl); —C₂-C₆ alkenyl;            —C₂-C₆ alkynyl; —C₁-C₆ alkyl chain with one double bond and            one triple bond; aryl; heteroaryl; heterocycloalkyl; or        -   R_(N-2), R_(N-3) and the nitrogen to which they are attached            form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl            group, wherein said heterocycloalkyl or heteroaryl group is            optionally fused to a benzene, pyridine, or pyrimidine ring,            and said groups are unsubstituted or substituted with 1, 2,            3, 4, or 5 groups that at each occurrence are independently            C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, halo C₁-C₆ alkyl, halo            C₁-C₆ alkoxy, —CN, —NO₂, —NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆            alkyl) (C₁-C₆ alkyl), —OH, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),            —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl), C₁-C₆ alkoxy C₁-C₆ alkyl,            C₁-C₆ thioalkoxy, and C₁-C₆ thioalkoxy C₁-C₆ alkyl;    -   or wherein,-   R₂, R₃ and the carbon to which they are attached form a carbocycle    of three thru seven carbon atoms, wherein one carbon atom is    optionally replaced by a group selected from —O—, —S—, —SO₂—, or    —NR_(N-2)—.

The invention also provides methods for the treatment or prevention ofAlzheimer's disease, mild cognitive impairment Down's syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, other degenerative dementias, dementias ofmixed vascular and degenerative origin, dementia associated withParkinson's disease, dementia associated with progressive supranuclearpalsy, dementia associated with cortical basal degeneration, diffuseLewy body type of Alzheimer's disease compriseing administration of atherapeutically effective amount of a compound or salt or ester offormula I, to a patient in need thereof.

Preferably, the patient is a human.

More preferably, the disease is Alzheimer's disease.

More preferably, the disease is dementia.

The invention also provides pharmaceutical compositions comprising acompound or salt or ester of formula I and at least one pharmaceuticallyacceptable carrier, solvent, adjuvant or diluent.

The invention also provides the use of a compound or salt or esteraccording to formula I for the manufacture of a medicament.

The invention also provides the use of a compound or salt or ester offormula I for the treatment or prevention of Alzheimer's disease, mildcognitive impairment Down's syndrome, Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, otherdegenerative dementias, dementias of mixed vascular and degenerativeorigin, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, or diffuse Lewy body type of Alzheimer'sdisease.

The invention also provides compounds, pharmaceutical compositions,kits, and methods for inhibiting beta-secretase-mediated cleavage ofamyloid precursor protein (APP). More particularly, the compounds,compositions, and methods of the invention are effective to inhibit theproduction of A-beta peptide and to treat or prevent any human orveterinary disease or condition associated with a pathological form ofA-beta peptide.

The compounds, compositions, and methods of the invention are useful fortreating humans who have Alzheimer's Disease (AD), for helping preventor delay the onset of AD, for treating patients with mild cognitiveimpairment (MCI), and preventing or delaying the onset of AD in thosepatients who would otherwise be expected to progress from MCI to AD, fortreating Down's syndrome, for treating Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type, for treating cerebral beta-amyloidangiopathy and preventing its potential consequences such as single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, fortreating dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, and diffuse Lewy body type AD, and fortreating frontotemporal dementias with parkinsonism (FTDP).

The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the invention isreadily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

Unless the substituents for a particular formula are expressly definedfor that formula, they are understood to carry the definitions set forthin connection with the preceding formula to which the particular formulamakes reference.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods. Moreparticularly, the invention provides a method for making a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof,wherein R₂₀, R₁, R₂, R₃, Rn and Rc are as defined above or below.

The invention further contemplates metabolites of compounds of formula(I).

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the invention provides compounds of formula I.

Preferred compounds of formula I include those of formula I-1, i.e.,compounds of formula I wherein, R_(N) is

-   -   wherein    -   R₄ is selected from the group consisting of H; NH₂;        —NH—(CH₂)_(n6)—R₄₋₁—NHR₈; —NR₅₀C(O)R₅; C₁-C₄ alkyl —NHC(O)R₅;        —(CH₂)₀₋₄R₈; —O—C₁-C₄ alkanoyl; OH; C₆-C₁₀ aryloxy optionally        substituted with 1, 2, or 3 groups that are independently        halogen, C₁-C₄ alkyl, —CO₂H, —C(O)—C₁-C₄ alkoxy, or C₁-C₄        alkoxy; C₁-C₆ alkoxy; aryl C₁-C₄ alkoxy; —NR₅₀CO₂R₅₁; —C₁-C₄        alkyl-NR₅OCO₂R₅₁; —C≡N; —CF₃; —CF₂—CF₃; —C≡CH; —CH₂—CH═CH₂;        —(CH₂)₁₋₄—R₄₁; —(CH₂)₁₋₄—NH—R₄₋₁; —O—(CH₂)_(n6)—R₄₋₁;        —S—(CH₂)_(n6)—R₄₋₁; —(CH₂)₀₋₄—NHC(O)—(CH₂)₀₋₆—R₅₂;        —(CH₂)₀₋₄—R₅₃—(CH₂)₀₋₄—R₅₄;    -   wherein        -   n₆ is 0, 1, 2, or 3;        -   n₇ is 0, 1, 2, or 3;    -   R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈        alkyl), —SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆        alkyl), —SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄;    -   R₄₋₂ and R₄₋₃ are independently H, C₁-C₃ alkyl, or C₃-C₆        cycloalkyl;    -   R₄₋₄ is alkyl, arylalkyl, alkanoyl, or arylalkanoyl;    -   R₄₋₆ is —H or C₁-C₆ alkyl;    -   R₅ is selected from the group consisting of C₃-C₇ cycloalkyl;        C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that        are independently halogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆        heterocycloalkyl, C₅-C₆ heteroaryl, C₆-C₁₀ aryl, C₃-C₇        cycloalkyl C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄ alkyl, —CO₂H,        —CONR₆R₇, —CO₂—C₁-C₄ alkyl, C₆-C₁₀ aryloxy; heteroaryl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄        haloalkyl, or OH; heterocycloalkyl optionally substituted with        1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, or C₂-C₄ alkanoyl; aryl optionally substituted        with 1, 2, 3, or 4 groups that are independently halogen, OH,        C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkyl; and —NR₆R₇;        wherein        -   R₆ and R₇ are independently selected from the group            consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl,            —SO₂—C₁-C₄ alkyl, phenyl C₁-C₄ alkyl;    -   R₈ is selected from the group consisting of —SO₂-heteroaryl,        —SO₂-aryl, —SO₂-heterocycloalkyl, —SO₂—C₁-C₁₀ alkyl, —C(O)NHR₉,        heterocycloalkyl, —S—C₁-C₆ alkyl, —S—C₂-C₄ alkanoyl, wherein        -   R₉ is aryl C₁-C₄ alkyl, C₁-C₆ alkyl, or H;    -    R₅₀ is H or C₁-C₆ alkyl;    -   R₅₁ is selected from the group consisting of aryl C₁-C₄ alkyl;        C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that        are independently halogen, cyano, heteroaryl, —NR₆R₇,        —C(O)NR₆R₇, C₃-C₇ cycloalkyl, or —C₁-C₄ alkoxy; heterocycloalkyl        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₂-C₄ alkanoyl, aryl C₁-C₄        alkyl, and —SO₂ C₁-C₄ alkyl; alkenyl; alkynyl; heteroaryl        optionally substituted with 1, 2, or 3 groups that are        independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂,        NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); heteroarylalkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆        alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); aryl; heterocycloalkyl;        C₁-C₆ cycloalkyl; and cycloalkylalkyl; wherein the aryl;        heterocycloalkyl, C₃-C₈ cycloalkyl, and cycloalkylalkyl groups        are optionally substituted with 1, 2, 3, 4 or 5 groups that are        independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆        alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆        thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy;    -   R₅₂ is heterocycloalkyl, heteroaryl, aryl, cycloalkyl,        —S(O)₀₋₂—C₁-C₆ alkyl, CO₂H, —C(O)NH₂, —C(O)NH(alkyl),        —C(O)N(alkyl)(alkyl), —CO₂-alkyl, —NHS(O)₀₋₂-C₁-C₆ alkyl,        —N(alkyl)S(O)₀₋₂—C₁-C₆ alkyl, —S(O)₀₋₂-heteroaryl,        —S(O)₀₋₂-aryl, —NH(arylalkyl), —N(alkyl)(arylalkyl), thioalkoxy,        or alkoxy, each of which is optionally substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, alkoxy, thioalkoxy,        halogen, haloalkyl, haloalkoxy, alkanoyl, NO₂, CN,        alkoxycarbonyl, or aminocarbonyl;    -   R₅₃ is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O)₀₋₂—,        —N(alkyl)-S(O)₀₋₂—, —S(O)₀₋₂—NH—, —S(O)₀₋₂—N(alkyl)-, —NH—C(S)—,        or —N(alkyl)-C(S)—;    -   R₅₄ is heteroaryl, aryl, arylalkyl, heterocycloalkyl, CO₂H,        —CO₂-alkyl, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —C(O)NH₂,        C₁-C₈ alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH₂, NH(alkyl),        N(alkyl) (alkyl), or —C₁-C₆ alkyl-CO₂—C₁-C₆ alkyl, each of which        is optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently alkyl, alkoxy, CO₂H, —CO₂-alkyl, thioalkoxy,        halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO₂, CN,        alkoxycarbonyl, or aminocarbonyl;    -   X′ is selected from the group consisting of —C₁-C₆ alkylidenyl        optionally optionally substituted with 1, 2, or 3 methyl groups;        and —NR₄₋₆—; or    -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, wherein        -   n₁₀ is 1, 2, 3, or 4;    -   Z is selected from the group consisting of a bond; SO₂; SO; S;        and C(O);    -   Y is selected from the group consisting of H; C₁-C₄ haloalkyl;        C₅-C₆ heterocycloalkyl; C₆-C₁₀ aryl; OH; —N(Y₁) (Y₂); C₁-C₁₀        alkyl optionally substituted with 1 thru 3 substituents which        can be the same or different and are selected from the group        consisting of halogen, hydroxy, alkoxy, thioalkoxy, and        haloalkoxy; C₃-C₈ cycloalkyl optionally substituted with 1, 2,        or 3 groups independently selected from C₁-C₃ alkyl, and        halogen; alkoxy; aryl optionally substituted with halogen,        alkyl, alkoxy, CN or NO₂; arylalkyl optionally substituted with        halogen, alkyl, alkoxy, CN or NO₂; wherein    -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyl        optionally substituted with 1, 2, or 3 substituents selected        from the group consisting of halogen, C₁-C₄ alkoxy, C₃-C₈        cycloalkyl, and OH; C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl;        —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄ alkyl; or C₃-C₈ cycloalkyl C₁-C₄        alkyl; or    -   Y₁, Y₂ and the nitrogen to which they are attached form a ring        selected from the group consisting of piperazinyl, piperidinyl,        morpholinyl, and pyrolidinyl, wherein each ring is optionally        substituted with 1, 2, 3, or 4 groups that are independently        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula I-1 also include those wherein R_(N) is

wherein

-   -   X′ is C₁-C₄ alkylidenyl optionally substituted with 1, 2, or 3        methyl groups; or —NR₄₋₆—, where R₄₋₆ is —H or C₁-C₆ alkyl; or        -   R₄ and R₄₋₆ combine to form —(CH₂)_(n10)—, where R₄ and R₄₋₆            are as defined above, wherein        -   n₁₀ is 1, 2, 3, or 4;    -   Z is selected from a bond; SO₂; SO; S; and C(O);        -   Y is selected from H; C₁-C₄ haloalkyl; C₅-C₆            heterocycloalkyl containing at least one N, O, or S; phenyl;            OH; —N(Y₁)(Y₂); C₁-C₁₀ alkyl optionally substituted with 1            thru 3 substituents which can be the same or different and            are selected from halogen, hydroxy, alkoxy, thioalkoxy, and            haloalkoxy; C₃-C₈ cycloalkyl optionally substituted with 1,            2, or 3 groups independently selected from C₁-C₃ alkyl, and            halogen; alkoxy; phenyl optionally substituted with halogen,            C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; phenyl C₁-C₄ alkyl            optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄            alkoxy, CN or NO₂; wherein            -   Y₁ and Y₂ are the same or different and are H; C₁-C₁₀                alkyl optionally substituted with 1, 2, or 3                substituents selected from the group consisting of                halogen, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, and OH; C₂-C₆                alkenyl; C₂-C₆ alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl;                phenyl C₁-C₄ alkyl; and C₃-C₈ cycloalkyl C₁-C₄ alkyl; or    -   —N(Y₁) (Y₂) forms a ring selected from piperazinyl, piperidinyl,        morpholinyl, and pyrolidinyl, wherein each ring is optionally        substituted with 1, 2, 3, or 4 groups that are independently        C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or halogen.

Preferred compounds of formula I-1 also include those wherein R_(N) is—C(═O)O—(C₁-C₆ alkyl)-aryl, wherein the aryl group may be substitutedwith R₁₀₀ or R′₁₀₀, which are defined as above. In other embodiment, RNis —C(═O)O—CH₂-phenyl.

Preferred compounds of formula I also include compounds of formula I-2,i.e., compounds of formula I wherein

-   R_(N) is —C(═O)—(CRR′)₀₋₆R₁₀₀; and-   R₁₀₀ represents aryl, heteroaryl, or heterocyclyl, where the ring    portions of each are optionally substituted with 1, 2, or 3 groups    independently selected from    -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,        —(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,        —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),        —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),        —(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,        —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,        —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,        —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R₁₀₅,        —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),        —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),        —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,        —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,        —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆        alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,        —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),        —(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),        —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)        alkenyl, or (C₂-C₁₀) alkynyl.

Preferred compounds of formula I-2 include compounds wherein

-   R_(N) is —C(═O)—R₁₀₀; and-   R₁₀₀ represents aryl, or heteroaryl, where the ring portions of each    are optionally substituted with 1, 2, or 3 groups independently    selected from    -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,        —(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,        —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),        —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),        —(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀,        —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,        —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,        —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—S₂—NR₁₀₅R′₁₀₅—(CH₂)₀₋₄—SO—(C₁-C₈        alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),        —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),        —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,        —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,        —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆        alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,        —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),        —(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀),        —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,        (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

Preferred compounds of formula I-2 also include compounds wherein

-   R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl where the ring portions of    each are optionally substituted with 1, 2, or 3 groups independently    selected from    -   —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,        —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,        —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),        —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,        —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀,        —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀,        —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl),        —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,        —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,        —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆        alkyl), —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),        —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,        (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

Other preferred compounds of formula I-2 include compounds wherein

-   R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl where the ring portions of    each are optionally substituted with 1 or 2 groups independently    selected from    -   C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,        —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,        —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl,        —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀)        alkynyl.

Other preferred compounds of formula I-2 also include compounds whereinR_(N) is:

-   wherein sub is hydrogen or is C₁-C₆ alkyl, halogen,    —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,    —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, C₃-C₇    cycloalkyl, —(C₂-C₁₀)alkenyl, —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,    —(CH₂)₀₋₄—R₁₃₀, or (C₂-C₁₀) alkynyl.

Preferred compounds of formula I, formula I-1 and formula I-2 includecompounds of formula I-3, i.e., compounds of formula I, I-1 or I-2wherein:

-   -   R₁ is (CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero, one, or two and        R_(1-aryl) is phenyl optionally substituted with 1, 2, 3, or 4        groups independently selected from C₁-C₆ alkyl optionally        substituted with 1, 2, or 3 substituents selected from the group        consisting of C₁-C₃ alkyl, halogen, —OH, —SH, —NR_(1-a)R_(1-b),        —C≡N, —CF₃, and C₁-C₃ alkoxy; halogen; C₁-C₆ alkoxy; —NRN-₂RN-₃;        and OH; wherein        -   R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl;        -   R_(N-2) and R_(N-3) at each occurrence are independently            selected from the group consisting of —C₁-C₈ alkyl            optionally substituted with 1, 2, or 3 groups independently            selected from the group consisting of —OH, —NH₂, phenyl and            halogen; —C₃-C₈ cycloalkyl; —(C₁-C₂ alkyl)-(C₃-C₈            cycloalkyl); —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl); —C₂-C₆ alkenyl;            —C₂-C₆ alkynyl; —C₁-C₆ alkyl chain with one double bond and            one triple bond; aryl; heteroaryl; heterocycloalkyl; or            -   R_(N-2), R_(N-3) and the nitrogen to which they are                attached form a 5, 6, or 7 membered heterocycloalkyl or                heteroaryl group, wherein said heterocycloalkyl or                heteroaryl group is optionally fused to a benzene,                pyridine, or pyrimidine ring, and said groups are                unsubstituted or substituted with 1, 2, 3, 4, or 5                groups that at each occurrence are independently C₁-C₆                alkyl, C₁-C₆ alkoxy, halogen, halo C₁-C₆ alkyl, halo                C₁-C₆ alkoxy, —CN, —NO₂, —NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆                alkyl) (C₁-C₆ alkyl), —OH, —C(O)NH₂, —C(O)NH(C₁-C₆                alkyl), —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl), C₁-C₆ alkoxy                C₁-C₆ alkyl, C₁-C₆ thioalkoxy, and C₁-C₆ thioalkoxy                C₁-C₆ alkyl.

Preferred compounds of formula I-3 include compounds wherein:

-   -   R₁ is aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆        alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring        portions of each are optionally substituted with 1, 2, 3, or 4        groups independently selected from halogen, —OH, —SH, —C≡N,        —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′ (where R₁₀₅,        R′₁₀₅, R and R′ are as defined above), —C(═O)—(C₁-C₄) alkyl,        —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino, —C(═O)-mono        or dialkylamino, —SO₂—(C₁-C₄) alkyl, or        -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups            which are independently selected from halogen, or        -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3            groups independently selected from halogen, —OH, —SH, —C≡N,            —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or            dialkylamino, or        -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups            independently selected from halogen, —OH, —SH, —C≡N, —CF₃,            —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃            alkyl, or        -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally            substituted with 1, 2, or 3 groups independently selected            from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino,            C₁-C₆ alkyl and mono- or dialkylamino; and the heterocyclyl            group is optionally further substituted with oxo.

Preferred compounds of formula I-3 include compounds wherein:

-   R₁ is —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or —C₁-C₆    alkyl-heterocyclyl, where the ring portions of each are optionally    substituted with 1, 2, 3, or 4 groups independently selected from    halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or    —N(R)SO₂R′ (where R₁₀₅, R′₁₀₅, R and R′ are as defined above),    —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or dialkylamino,    —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or    -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which        are independently selected from halogen, or    -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally        substituted with 1, 2, or 3 groups independently selected from        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl        and mono- or dialkylamino; and the heterocyclyl group is        optionally further substituted with oxo.

Preferred compounds of formula I-3 include compounds wherein:

-   R₁ is —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, or    —(CH₂)_(n)-heterocyclyl, where n is one or two and where the ring    portions of each are optionally substituted with 1, 2, 3, or 4    groups independently selected from halogen, —OH, —SH, —C≡N, —NO₂,    —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′ (where R₁₀, R′₁₀₅, R    and R′ are as defined above), —C(═O)—(C₁-C₄) alkyl, —SO₂-amino,    —SO₂-mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or    dialkylamino, —SO₂—(C₁-C₄) alkyl, or    -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which        are independently selected from halogen, or    -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, —C₁-C₆ alkyl and mono- or dialkylamino, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally        substituted with 1, 2, or 3 groups independently selected from        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl        and mono- or dialkylamino; and the heterocyclyl group is        optionally further substituted with oxo.

Preferred compounds of formula I-3 include compounds wherein:

-   R₁ is —(CH₂)_(n)-phenyl or —(CH₂)_(n)-pyridinyl where n is one or    two and where the ring portions of each are optionally substituted    with 1, 2, 3, or 4 groups independently selected from halogen, C₁-C₄    alkoxy, hydroxy, —NO₂, and    -   C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituents        independently selected from halogen, OH, SH, NH₂, NH(C₁-C₆        alkyl), N—(C₁-C₆ alkyl) (C₁-C₆ alkyl), C≡N, CF₃.

Preferred compounds of formula I-3 include compounds wherein: R₁ is—(CH₂)_(n)-phenyl or —(CH₂)_(n)-pyridinyl where n is one or two andwhere the phenyl or pyridinyl rings are each optionally substituted with1 or 2 groups independently selected from halogen, C₁-C₂ alkyl, C₁-C₂alkoxy, hydroxy, —CF₃, and —NO₂.

Preferred compounds of formula I-3 include compounds wherein: R₁ is—CH₂-phenyl or —CH₂CH₂-phenyl where the phenyl ring is optionallysubstituted with 2 groups independently selected from halogen, C₁-C₂alkyl, C₁-C₂ alkoxy, hydroxy, and NO₂.

Preferred compounds of formula I-3 include compounds wherein: R₁ isbenzyl, 3,5-difluorobenzyl, or 2-(3,5-difluorophenyl)ethyl.

Preferred compounds of formula I-1, I-2, and I-3 also include compoundsof formula I-4, i.e., those of formula I-1, I-2, or I-3 wherein:

-   R_(C) is hydrogen, —(CR₂₄₅R₂₅₀)₀₋₄-aryl, —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl,    -   C₂-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from the group consisting of R₂₀₅, R₁₁₀,        R₁₂₀, R₁₃₀′—OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂(C₁-C₆ alkyl), —SH, and        —S(═O)₂NR₂₃₅R₂₄₀,    -   —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is        optionally substituted with 1, 2, or 3 groups independently        selected from the group consisting of R₂₀₅, —CO₂H, and        —CO₂—(C₁-C₄ alkyl), or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionally        substituted with 1, 2, or 3 independently selected R₂₀₅ groups,        wherein    -   each aryl and heteroaryl is optionally substituted with 1, 2, or        3 R₂₀₀, and wherein each heterocyclyl is optionally substituted        with 1, 2, 3, or 4 independently selected R₂₁₀ groups.

Preferred compounds of formula I-4 also include compounds wherein

-   R_(C) is —(CR₂₄₅R₂₅₀)-aryl, —(CR₂₄₅R₂₅₀)-heteroaryl,    —(CR₂₄₅R₂₅₀)-heterocyclyl,    -   C₂-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from the group consisting of R₂₀₅, R₁₁₀,        R₁₂₀, R₁₃₀, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆ alkyl), —SH, and        —S(═O)₂NR₂₃₅R₂₄₀, wherein    -   each aryl and heteroaryl is optionally substituted with 1, 2, or        3 R₂₀₀, and wherein each heterocyclyl is optionally substituted        with 1, 2, 3, or 4 independently selected R₂₁₀ groups.

Preferred compounds of formula I-4 also include compounds wherein

-   R_(C) is —(CH₂)-aryl, —(CH₂)-heteroaryl, or    -   C₂-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from C₁-C₆ alkyl, halogen, —OH,        —O-phenyl, —SH, —S—C₁-C₆ alkyl, —C—N, —CF₃, C₁-C₆ alkoxy, and        NH₂, wherein    -   each aryl and heteroaryl is optionally substituted with 1, 2, or        3 groups selected from OH, —NO₂, halogen, —CO₂H, C≡N,        —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), and        —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅.

Preferred compounds of formula I-4 also include compounds wherein

-   R_(C) is —(CH₂)-phenyl, wherein phenyl is optionally substituted    with 1, 2, or 3 groups selected from OH, —NO₂, halogen, —CO₂H, and    C≡N, or-   R_(C) is C₂-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups    independently selected from C₁-C₆ alkyl, halogen, —OH, —C≡N, —CF₃,    C₁-C₆ alkoxy, and NH₂.

Preferred compounds of formula I-4 also include compounds wherein R_(C)is benzyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl or iso-butyl.

Preferred compounds of the formula I-4 also include those wherein:

-   R_(C) is    wherein x₁, x₂, and x₃ are independently —CHR₂₄₅, SO₂, or NH, and    wherein the phenyl ring is optionally substituted with 1 or 2 —R₂₄₅    groups.

More preferred compounds of the formula I-6 also include those whereinone of x₁, x₂, or x₃ is SO₂.

More preferred compounds of the formula I-6 also include those whereinone of x₁, x₂, or x₃ is NH.

More preferred compounds of the formula I-6 also include those whereinx₁, x₂, and x₃ are each CH₂.

Preferred compounds of formula I-1, I-2, I-3, and I-4, also includecompounds of formula I-5, i.e., those of formula I-1, I-2, I-3, or I-4wherein each of R₂, R₃, and R₂₀ are independently hydrogen.

The invention also provides methods for treating a patient who has, orin preventing a patient from getting, a disease or condition selectedfrom the group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, or diffuse Lewy body typeof Alzheimer's disease and who is in need of such treatment, comprisingadministering to such patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt or esterthereof, wherein R₂₀, R₁, R₂, R₃, R_(N) and R_(C) are as defined aboveor below.

In an embodiment, this method of treatment can be used where the diseaseis Alzheimer's disease.

In an embodiment, this method of treatment can help prevent or delay theonset of Alzheimer's disease.

In an embodiment, this method of treatment can be used where the diseaseis mild cognitive impairment.

In an embodiment, this method of treatment can be used where the diseaseis Down's syndrome.

In an embodiment, this method of treatment can be used where the diseaseis Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.

In an embodiment, this method of treatment can be used where the diseaseis cerebral amyloid angiopathy.

In an embodiment, this method of treatment can be used where the diseaseis degenerative dementias.

In an embodiment, this method of treatment can be used where the diseaseis diffuse Lewy body type of Alzheimer's disease.

In an embodiment, this method of treatment can treat an existingdisease.

In an embodiment, this method of treatment can prevent a disease fromdeveloping.

In an embodiment, this method of treatment can employ therapeuticallyeffective amounts: for oral administration from about 0.1 mg/day toabout 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecaladministration from about 0.5 to about 100 mg/day; for depoadministration and implants from about 0.5 mg/day to about 50 mg/day;for topical administration from about 0.5 mg/day to about 200 mg/day;for rectal administration from about 0.5 mg to about 500 mg.

In an embodiment, this method of treatment can employ therapeuticallyeffective amounts: for oral administration from about 1 mg/day to about100 mg/day; and for parenteral administration from about 5 to about 50mg daily.

In an embodiment, this method of treatment can employ therapeuticallyeffective amounts for oral administration from about 5 mg/day to about50 mg/day.

The invention also includes pharmaceutical compositions which include acompound of formula (I) or a pharmaceutically acceptable salt or esterthereof.

The invention also includes the use of a compound of formula (I) orpharmaceutically acceptable salts or esters thereof for the manufactureof a medicament for use in treating a patient who has, or in preventinga patient from getting, a disease or condition selected from the groupconsisting of Alzheimer's disease, for helping prevent or delay theonset of Alzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is Alzheimer's disease.

In an embodiment, this use of a compound of formula (I) can help preventor delay the onset of Alzheimer's disease.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is mild cognitive impairment.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is Down's syndrome.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is Hereditary Cerebral Hemorrhage with Amyloidosis ofthe Dutch-Type.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is cerebral amyloid angiopathy.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is degenerative dementias.

In an embodiment, this use of a compound of formula (I) can be employedwhere the disease is diffuse Lewy body type of Alzheimer's disease.

In an embodiment, this use of a compound employs a pharmaceuticallyacceptable salt selected from the group consisting of salts of thefollowing acids hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,phosphoric, citric, methanesulfonic, CH₃—(CH₂)_(n)—COOH where n is 0thru 4, HOOC—(CH₂)_(n)—COOH where n is as defined above,HOOC—CH═CH—COOH, and phenyl-COOH.

The invention also includes methods for inhibiting beta-secretaseactivity, for inhibiting cleavage of amyloid precursor protein (APP), ina reaction mixture, at a site between Met596 and Asp597, numbered forthe APP-695 amino acid isotype, or at a corresponding site of an isotypeor mutant thereof; for inhibiting production of amyloid beta peptide (Abeta) in a cell; for inhibiting the production of beta-amyloid plaque inan animal; and for treating or preventing a disease characterized bybeta-amyloid deposits in the brain. These methods each includeadministration of a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or ester thereof.

The invention also includes a method for inhibiting beta-secretaseactivity, including exposing said beta-secretase to an effectiveinhibitory amount of a compound of formula (I), or a pharmaceuticallyacceptable salt or ester thereof.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of less than 200 micromolar.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of less than 50 micromolar.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 10 micromolar or less.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 1 micromolar or less.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in vitro.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in a cell.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in a cell in an animal.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in a human.

The invention also includes a method for inhibiting cleavage of amyloidprecursor protein (APP), in a reaction mixture, at a site between Met596and Asp597, numbered for the APP-695 amino acid isotype; or at acorresponding site of an isotype or mutant thereof, including exposingsaid reaction mixture to an effective inhibitory amount of a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof.

In an embodiment, this method employs a cleavage site: between Met652and Asp653, numbered for the APP-751 isotype; between Met 671 and Asp672, numbered for the APP-770 isotype; between Leu596 and Asp597 of theAPP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751Swedish Mutation; or between Leu671 and Asp672 of the APP-770 SwedishMutation.

In an embodiment, this method exposes said reaction mixture in vitro.

In an embodiment, this method exposes said reaction mixture in a cell.

In an embodiment, this method exposes said reaction mixture in an animalcell.

In an embodiment, this method exposes said reaction mixture in a humancell.

The invention also includes a method for inhibiting production ofamyloid beta peptide (A beta) in a cell, including administering to saidcell an effective inhibitory amount of a compound of formula (I), or apharmaceutically acceptable salt or ester thereof.

In an embodiment, this method includes administering to an animal.

In an embodiment, this method includes administering to a human.

The invention also includes a method for inhibiting the production ofbeta-amyloid plaque in an animal, including administering to said animalan effective inhibitory amount of a compound of formula (I), or apharmaceutically acceptable salt or ester thereof.

In an embodiment, this method includes administering to a human.

The invention also includes a method for treating or preventing adisease characterized by beta-amyloid deposits in the brain includingadministering to a patient an effective therapeutic amount of a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of less than 50 micromolar.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 10 micromolar or less.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 1 micromolar or less.

In an embodiment, this method employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 10 nanomolar or less.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 0.1 to about 1000 mg/day.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 15 to about 1500 mg/day.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 1 to about 100 mg/day.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 5 to about 50 mg/day.

In an embodiment, this method can be used where said disease isAlzheimer's disease.

In an embodiment, this method can be used where said disease is MildCognitive Impairment, Down's Syndrome, or Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type.

The invention also includes a composition including beta-secretasecomplexed with a compound of formula (I), or a pharmaceuticallyacceptable salt or ester thereof.

The invention also includes a method for producing a beta-secretasecomplex including exposing beta-secretase to a compound of formula (I),or a pharmaceutically acceptable salt or ester thereof, in a reactionmixture under conditions suitable for the production of said complex.

In an embodiment, this method employs exposing in vitro.

In an embodiment, this method employs a reaction mixture that is a cell.

The invention also includes a component kit including component partscapable of being assembled, in which at least one component partincludes a compound of formula I enclosed in a container.

In an embodiment, this component kit includes lyophilized compound, andat least one further component part includes a diluent.

The invention also includes a container kit including a plurality ofcontainers, each container including one or more unit dose of a compoundof formula (I), or a pharmaceutically acceptable salt or ester thereof.

In an embodiment, this container kit includes each container adapted fororal delivery and includes a tablet, gel, or capsule.

In an embodiment, this container kit includes each container adapted forparenteral delivery and includes a depot product, syringe, ampoule, orvial.

In an embodiment, this container kit includes each container adapted fortopical delivery and includes a patch, medipad, ointment, or cream.

The invention also includes an agent kit including a compound of formula(I), or a pharmaceutically acceptable salt or ester thereof; and one ormore therapeutic agent selected from the group consisting of anantioxidant, an anti-inflammatory, a gamma secretase inhibitor, aneurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an Abeta peptide, and an anti-A beta antibody.

The invention also includes a composition including a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof, andan inert diluent or edible carrier.

In an embodiment, this composition includes a carrier that is an oil.

The invention also includes a composition including: a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof, anda binder, excipient, disintegrating agent, lubricant, or gildant.

The invention also includes a composition including a compound offormula (I), or a pharmaceutically acceptable salt or ester thereof;disposed in a cream, ointment, or patch.

The invention provides compounds of formula (I) that are useful intreating and preventing Alzheimer's disease. The compounds of theinvention can be prepared by one skilled in the art based only onknowledge of the compound's chemical structure. The chemistry for thepreparation of the compounds of this invention is known to those skilledin the art. In fact, there is more than one process to prepare thecompounds of the invention. Specific examples of methods of preparationcan be found in the art. For examples, see J. Org. Chem. 1998, 63,4898-4906; J. Org. Chem. 1997, 62, 9348-9353; J. Org. Chem. 1996, 61,5528-5531; J. Med. Chem. 1993, 36, 320-330; J. Am. Chem. Soc. 1999, 121,1145-1155; and references cited therein. See also U.S. Pat. Nos.6,150,530, 5,892,052, 5,696,270, and 5,362,912, which are incorporatedherein by reference, and references cited therein.

The anti-Alzheimer's substituted alcohols (I) are made by methods wellknown to those skilled in the art from starting compounds known to thoseskilled in the art. The process chemistry is well known to those skilledin the art. The most general process to prepare the substituted aminoalcohols (I) of the invention is set forth below in Scheme I.

Scheme I describes the synthesis of compounds (VIII). The procedure isbased on that outlined in Tung, R. D., et al. U.S. Pat. No. 6,127,372.Compounds (II) and (III) were coupled according to standard couplingmethods or sulfonamide formation. The anion of compound (IV) was formed,and treated with compound (V) to form epoxide (VI). This epoxide wasthen ring-opened using amine (VII) to afford inhibitor (VIII).

The chemistry is straight forward and in summary involves the acylationor sulfonylation of an appropriate amine (III). The product (IV) isfurther used in the displacement of comercially available glycidyltosylate (V). The epoxide (VI) thus obtained was further reacted withthe amine VII to open the epoxide and yield the desired substitutedalcohol (VIII). One skilled in the art will appreciate that these areall well known reactions in organic chemistry. A chemist skilled in theart, knowing the chemical structure of the biologically activesubstituted alcohol end product (VIII) of the invention would be able toprepare them by known methods from known starting materials without anyadditional information.

Scheme I sets forth a general method used in the invention to preparethe appropriately substituted alcohols (I). The anti-Alzheimersubstituted alcohols of the invention are prepared by starting with theappropriately selected carboxylic acid or sulfonyl chloride (II). Thenitrogen-acylation of primary amines to produce secondary amides is oneof the oldest known reactions. In a general aspect of Scheme I, R_(N-1),or R_(N-2) or R_(N-3) are defined as is RN above or below. The amideforming agents, (R₁—X_(N))₂O or R_(N-1)—X_(N)—Cl or R_(N-1)—X_(N)—OH areknown to those skilled in the art and are commercially available or canbe readily prepared from known starting materials by methods known inthe literature. It is preferred to use an isophthalic acid acylatingagent (IX) of the formula R_(N-2)R_(N-3)N—CO-φ—CO— or amethylisophthalic acid acylating agent (X)R_(N-2)R_(N-3)N—CO—(CH₃—)φ-CO— where the substitution is5-methyl-1,3-isophthalic acid. These compounds are preferably preparedas set forth as follows. An ester, preferably the methyl ester ofisophthalate or methyl 5-methyl-1,3-isophthalate (1 equiv, 11.1 mmol) isdissolved in a THF/DMF mixture (1/1; 20 ml). 1,1′-carbonyldiimidazole(CDI, 1.2 equiv, 13.3 mmol) is added at 20-25°. Next the desired amine(H—NR_(N-2)R_(N-3); 1.2 equiv, 13.3 mmol) is added. After 12 hr ofstirring at 20-25°, the reaction mixture is partitioned betweensaturated aqueous ammonium chloride and a water immiscible organicsolvent such as ethyl acetate. The aqueous layer is separated andextracted twice more with the organic solvent (ethyl acetate). Theorganic extracts are combined and then washed with saturated aqueoussolutions of bicarbonate and saline and dried over anhydrous sodiumsulfate or magnesium sulfate. Filtration of the drying agent and removalof solvents by reduced pressure (with heat) gives crude methyl ester ofthe desired R_(N-2)R_(N-3)N—CO—O—CO—O—CH₃ or a methylisophthalic acidacylating agent (IX) R_(N-2)R_(N-3)N—CO—(CH₃—)φ-CO—O—CH₃. Purificationof the (methyl) ester can be achieved via chromatography on silica geleluting with 30-40% ethyl acetate in hexanes. The isophthalate ester ormethylisophthalate ester of the mono-alkyl or di-alkyl amide is thentreated with an aqueous solution of base such as lithium hydroxide (3equiv, 33.3 mmol) in a minimum amount of THF/methanol/water (1/2/1) andstirred overnight at 20-25°. After 12 hr, the solvents are removed underreduced pressure preferably with heat and subsequently partitionedbetween water and ethyl acetate. If emulsions prohibit separation of thetwo phases, a small amount of saline is added to aid in separation. Theaqueous phase is separated and extracted once more with ethyl acetate.The aqueous phase was then acidified with concentrated acid, preferablyhydrochloric until pH ≦3. The mixture obtained is then extracted threetimes with ethyl acetate. These combined organic extracts are dried overanhydrous sodium or magnesium sulfate. The drying agent is removed byfiltration and the organic solvent remove under reduced pressurepreferably with heat to gave crude product. The crude product is columnpurified and used for coupling with the amine (III) to give the desiredproduct (IV). This coupling can be done using CDI as described above.

The selected amine (III) is commercially available or can be readilyprepared from known compounds by either reductive amination of theappropriate aldehyde or reduction of a nitrile these are methods wellknown to those skilled in the art. Substituted epoxide tosylates (V) maybe synthesized from the corresponding allylic alcohols. The followingreference describes the asymmetric synthesis of epoxide alcohols fromallylic alcohols. The allylic alcohols may be available commercially orsynthesized according to references cited therein. Gao, Y.; Hanson, R.M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. CatalyticAsymmetric Epoxidation and Kinetic Resolution: Modified ProceduresIncluding in Situ Derivatization. J. Am. Chem. Soc. 1987, 109,5765-5780. The epoxide alcohols can then be readily converted to theepoxide tosylates: Klunder, Janice M.; Ko, Soo Y.; Sharpless, K. Barry.Asymmetric Epoxidation of Allyl Alcohol: Efficient Routes to Homochiralβ-Adrenergic Blocking Agents. J. Org. Chem. (1986), 51(19), 3710-12.

The epoxide (VI) is then reacted with the appropriately substitutedC-terminal amine, R_(C)—NH₂ (VII) by means known to those skilled in theart which opens the epoxide to produce the desired alcohol (VIII). Thesubstituted C-terminal amines, R_(C)—NH₂ (VI) of this invention arecommercially available or are known to those skilled in the art and canbe readily prepared from known compounds.

Suitable reaction conditions for opening the epoxide (VI) includerunning the reaction in a wide range of common and inert solvents. C₁-C₆alcohol solvents are preferred and isopropyl alcohol most preferred. Thereactions can be run at temperatures ranging from 20-25° up to thereflux temperature of the alcohol employed. The preferred temperaturerange for conducting the reaction is between 50° up to the refluxtemperature of the alcohol employed. When the substituted C-terminalamine (VII) is a 1-amino-3,5-cis-dimethyl cyclohexyldicarboxylate it ispreferably prepared as follows. To dimethyl-5-isophthalate in aceticacid and methanol, is added rhodium in alumina in a high-pressurebottle. The bottle is saturated with hydrogen at 55 psi and shaken forone week of time. The mixture is then filtered through a thick layer ofcelite cake and rinsed with methanol three times, the solvents areremoved under reduced pressure (with heat) to give a concentrate. Theconcentrate is triturated with ether and filtered again to give thedesired C-terminal amine (VI). When the substituted C-terminal amine(VII) is 1-amino-3,5-cis-dimethoxy cyclohexane it is preferablyfollowing the general procedure above and making non-critical variationsbut starting wth 3,5-dimethoxyaniline. When the substituted C-terminalamine (VII) is an aminomethyl group where the substituent on the methylgroup is an aryl group, for example NH₂—CH₂—R_(C-aryl), andNH₂—CH₂—R_(C-aryl) is not commercially available it is preferablyprepared as follows. A suitable starting material is the (appropriatelysubstituted) aralkyl compound. The first step is bromination of thealkyl substituent via methods known to those skilled in the art, see forexample R. C. Larock in Comprehensive organic Transformations, VCHPublishers, 1989, p. 313. Next the alkyl halide is reacted with azide toproduce the aryl-(alkyl)-azide. Last the azide is reduced to thecorresponding amine by hydrogen/catalyst to give the C-terminal amine(VII) of formula NH₂—CH₂—R_(C-aryl).

An alternative and exemplary preparation route for various compounds isshown below in Scheme II.

Another example of one of many various processes that can be used in thepreparation of intermediates for the preparation of compounds of theinvention is forth in Scheme III.

When utilized in the preparation of compounds of the invention, theprotection of amines is conducted, where appropriate, by methods knownto those skilled in the art. Amino protecting groups are known to thoseskilled in the art. See for example, “Protecting Groups in OrganicSynthesis”, John Wiley and sons, New York, N.Y., 1981, Chapter 7;“Protecting Groups in Organic Chemistry”, Plenum Press, New York, N.Y.,1973, Chapter 2. When the amino protecting group is no longer needed, itis removed by methods known to those skilled in the art. By definitionthe amino protecting group must be readily removable. A variety ofsuitable methodologies are known to those skilled in the art; see alsoT. W. Green and P. G. M. Wuts in “Protective Groups in OrganicChemistry, John Wiley and Sons, 1991. Suitable amino protecting groupsinclude t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,phthalimido, trichloro-acetyl, chloroacetyl, bromoacetyl, iodoacetyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)prop-2-yloxy-carbonyl, cyclopentanyloxycarbonyl,1-methylcyclo-pentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methyl-cyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)-ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxy-carbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobrornyloxycarbonyl, 1-piperidyloxycarbonyl, 9-fluoroenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.

It is preferred that the protecting group be t-butoxycarbonyl (BOC)and/or benzyloxycarbonyl (CBZ), it is more preferred that the protectinggroup be t-butoxycarbonyl. One skilled in the art will recognizesuitable methods of introducing a t-butoxycarbonyl or benzyloxycarbonylprotecting group and may additionally consult T. W. Green and P. G. M.Wuts in “Protective Groups in Organic Chemistry, John Wiley and Sons,1991 for guidance.

The compounds of the invention may contain geometric or optical isomersas well as tautomers. Thus, the invention includes all tautomers andpure geometric isomers, such as the E and Z geometric isomers, as wellas mixtures thereof. Further, the invention includes pure enantiomersand diastereomers as well as mixtures thereof, including racemicmixtures. The individual geometric isomers, enantiomers or diastereomersmay be prepared or isolated by methods known to those skilled in theart, including but not limited to chiral chromatography; preparingdiastereomers, separating the diastereomers and converting thediastereomers into enantiomers through the use of a chiral resolvingagent.

Compounds of the invention with designated stereochemistry can beincluded in mixtures, including racemic mixtures, with otherenantiomers, diastereomers, geometric isomers or tautomers. In apreferred aspect, compounds of the invention with (S, R, R), (S, S, S),or (S, R, S) stereochemistry are typically present in these mixtures inexcess of 50 percent. Preferably, compounds of the invention withdesignated stereochemistry are present in these mixtures in excess of 80percent. More preferably, compounds of the invention with designatedstereochemistry are present in these mixtures in excess of 90 percent.Even more preferably, compounds of the invention with designatedstereochemistry are present in these mixtures in excess of 99 percent.

Several of the compounds of formula (I) are amines, and as such formsalts when reacted with acids. Pharmaceutically acceptable salt oresters are preferred over the corresponding amines of formula (I) sincethey produce compounds, which are more water soluble, stable and/or morecrystalline. Pharmaceutically acceptable salts are any salt whichretains the activity of the parent compound and does not impart anydeleterious or undesirable effect on the subject to whom it isadministered and in the context in which it is administered.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The preferred pharmaceutically acceptable salts includesalts of the following acids acetic, aspartic, benzenesulfonic, benzoic,bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic,carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl,esylic, formic, fumaric, gluceptic, gluconic, glutamic,glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic,lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Forother acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) and J.Pharm. Sci., 66(1), 1, (1977).

The invention provides compounds, compositions, kits, and methods forinhibiting beta-secretase enzyme activity and A beta peptide production.Inhibition of beta-secretase enzyme activity halts or reduces theproduction of A beta from APP and reduces or eliminates the formation ofbeta-amyloid deposits in the brain.

Methods of the Invention

The compounds of the invention, and pharmaceutically acceptable salts oresters thereof, are useful for treating humans or animals suffering froma condition characterized by a pathological form of beta-amyloidpeptide, such as beta-amyloid plaques, and for helping to prevent ordelay the onset of such a condition. For example, the compounds areuseful for treating Alzheimer's disease, for helping prevent or delaythe onset of Alzheimer's disease, for treating patients with MCI (mildcognitive impairment) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobal hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, and diffuse Lewy body typeAlzheimer's disease. The compounds and compositions of the invention areparticularly useful for treating or preventing Alzheimer's disease. Whentreating or preventing these diseases, the compounds of the inventioncan either be used individually or in combination, as is best for thepatient.

As used herein, the term “treating” means that the compounds of theinvention can be used in humans with at least a tentative diagnosis ofdisease. The compounds of the invention will delay or slow theprogression of the disease thereby giving the individual a more usefullife span.

The term “preventing” means that the compounds of the invention areuseful when administered to a patient who has not been diagnosed aspossibly having the disease at the time of administration, but who wouldnormally be expected to develop the disease or be at increased risk forthe disease. The compounds of the invention will slow the development ofdisease symptoms, delay the onset of the disease, or prevent theindividual from developing the disease at all. Preventing also includesadministration of the compounds of the invention to those individualsthought to be predisposed to the disease due to age, familial history,genetic or chromosomal abnormalities, and/or due to the presence of oneor more biological markers for the disease, such as a known geneticmutation of APP or APP cleavage products in brain tissues or fluids.

In treating or preventing the above diseases, the compounds of theinvention are administered in a therapeutically effective amount. Thetherapeutically effective amount will vary depending on the particularcompound used and the route of administration, as is known to thoseskilled in the art.

In treating a patient displaying any of the diagnosed above conditions aphysician may administer a compound of the invention immediately andcontinue administration indefinitely, as needed. In treating patientswho are not diagnosed as having Alzheimer's disease, but who arebelieved to be at substantial risk for Alzheimer's disease, thephysician should preferably start treatment when the patient firstexperiences early pre-Alzheimer's symptoms such as, memory or cognitiveproblems associated with aging. In addition, there are some patients whomay be determined to be at risk for developing Alzheimer's through thedetection of a genetic marker such as APOE4 or other biologicalindicators that are predictive for Alzheimer's disease. In thesesituations, even though the patient does not have symptoms of thedisease, administration of the compounds of the invention may be startedbefore symptoms appear, and treatment may be continued indefinitely toprevent or delay the onset of the disease.

Dosage Forms and Amounts

The compounds of the invention can be administered orally, parenterally,(IV, IM, depo-IM, SQ, and depo SQ), sublingually, intranasally(inhalation), intrathecally, topically, or rectally. Dosage forms knownto those of skill in the art are suitable for delivery of the compoundsof the invention.

Compositions are provided that contain therapeutically effective amountsof the compounds of the invention. The compounds are preferablyformulated into suitable pharmaceutical preparations such as tablets,capsules, or elixirs for oral administration or in sterile solutions orsuspensions for parenteral administration. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art.

About 1 to 500 mg of a compound or mixture of compounds of the inventionor a physiologically acceptable salt or ester or ester is compoundedwith a physiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein those compositions or preparations is such that a suitable dosage inthe range indicated is obtained. The compositions are preferablyformulated in a unit dosage form, each dosage containing from about 2 toabout 100 mg, more preferably about 10 to about 30 mg of the activeingredient. The term “unit dosage from” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

To prepare compositions, one or more compounds of the invention aremixed with a suitable pharmaceutically acceptable carrier. Upon mixingor addition of the compound(s), the resulting mixture may be a solution,suspension, emulsion, or the like. Liposomal suspensions may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. The form of theresulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. The effective concentration issufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salt or ester orprodrugs may also be used in formulating effective pharmaceuticalcompositions.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are formulated for single dosage administration.

The compounds of the invention may be prepared with carriers thatprotect them against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, microencapsulateddelivery systems. The active compound is included in thepharmaceutically acceptable carrier in an amount sufficient to exert atherapeutically useful effect in the absence of undesirable side effectson the patient treated. The therapeutically effective concentration maybe determined empirically by testing the compounds in known in vitro andin vivo model systems for the treated disorder.

The compounds and compositions of the invention can be enclosed inmultiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound of theinvention. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampoules, vials, and the like forparenteral administration; and patches, medipads, creams, and the likefor topical administration.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent such as water for injection, saline solution, fixed oil,a naturally occurring vegetable oil such as sesame oil, coconut oil,peanut oil, cottonseed oil, and the like, or a synthetic fatty vehiclesuch as ethyl oleate, and the like, polyethylene glycol, glycerine,propylene glycol, or other synthetic solvent; antimicrobial agents suchas benzyl alcohol and methyl parabens; antioxidants such as ascorbicacid and sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid (EDTA); buffers such as acetates,citrates, and phosphates; and agents for the adjustment of tonicity suchas sodium chloride and dextrose. Parenteral preparations can be enclosedin ampoules, disposable syringes, or multiple dose vials made of glass,plastic, or other suitable material. Buffers, preservatives,antioxidants, and the like can be incorporated as required.

Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known for example, as described in U.S. Pat. No.4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time-releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

The compounds of the invention can be administered orally, parenterally(IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally(inhalation), intrathecally, topically, or rectally. Dosage forms knownto those skilled in the art are suitable for delivery of the compoundsof the invention.

Compounds of the invention may be administered enterally orparenterally. When administered orally, compounds of the invention canbe administered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions, and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily.

The oral dosage forms are administered to the patient 1, 2, 3, or 4times daily. It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily. Hence, it is preferred that the compounds of the invention beadministered in oral dosage form. It is preferred that whatever oraldosage form is used, that it be designed so as to protect the compoundsof the invention from the acidic environment of the stomach. Entericcoated tablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art.

When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges. In certain embodiments and situations, it may be necessary toadminister up to about 10 mg/kg or 30 mg/kg of the compound per day,resulting in dosages of about, for example, 1500 mg/day or even about2500 mg/day, either in one dose or two doses per day.

Compounds of the invention may also be advantageously delivered in anano crystal dispersion formulation. Preparation of such formulations isdescribed, for example, in U.S. Pat. No. 5,145,684. Nano crystallinedispersions of HIV protease inhibitors and their method of use aredescribed in U.S. Pat. No. 6,045,829. The nano crystalline formulationstypically afford greater bioavailability of drug compounds.

The compounds of the invention can be administered parenterally, forexample, by IV, IM, depo-IM, SC, or depo-SC. When administeredparenterally, a therapeutically effective amount of about 0.5 to about100 mg/day, preferably from about 5 to about 50 mg daily should bedelivered. When a depot formulation is used for injection once a monthor once every two weeks, the dose should be about 0.5 mg/day to about 50mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In partbecause of the forgetfulness of the patients with Alzheimer's disease,it is preferred that the parenteral dosage form be a depo formulation.

The compounds of the invention can be administered sublingually. Whengiven sublingually, the compounds of the invention should be given oneto four times daily in the amounts described above for IMadministration.

The compounds of the invention can be administered intranasally. Whengiven by this route, the appropriate dosage forms are a nasal spray ordry powder, as is known to those skilled in the art. The dosage of thecompounds of the invention for intranasal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered intrathecally. Whengiven by this route the appropriate dosage form can be a parenteraldosage form as is known to those skilled in the art. The dosage of thecompounds of the invention for intrathecal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered topically. When givenby this route, the appropriate dosage form is a cream, ointment, orpatch. Because of the amount of the compounds of the invention to beadministered, the patch is preferred. When administered topically, thedosage is from about 0.5 mg/day to about 200 mg/day. Because the amountthat can be delivered by a patch is limited, two or more patches may beused. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the compounds ofthe invention be delivered as is known to those skilled in the art. Thecompounds of the invention can be administered rectally by suppositoryas is known to those skilled in the art. When administered bysuppository, the therapeutically effective amount is from about 0.5 mgto about 500 mg.

The compounds of the invention can be administered by implants as isknown to those skilled in the art. When administering a compound of theinvention by implant, the therapeutically effective amount is the amountdescribed above for depot administration.

Given a particular compound of the invention and a desired dosage form,one skilled in the art would know how to prepare and administer theappropriate dosage form.

The compounds of the invention are used in the same manner, by the sameroutes of administration, using the same pharmaceutical dosage forms,and at the same dosing schedule as described above, for preventingdisease or treating patients with MCI (mild cognitive impairment) andpreventing or delaying the onset of Alzheimer's disease in those whowould progress from MCI to AD, for treating or preventing Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type of Alzheimer's disease.

The compounds of the invention can be used in combination, with eachother or with other therapeutic agents or approaches used to treat orprevent the conditions listed above. Such agents or approaches include:acetylcholine esterase inhibitors such as tacrine(tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride,(marketed as Aricept® and rivastigmine (marketed as Exelon®);gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and otherneurotropic agents of the future.

In addition, the compounds of formula (I) can also be used withinhibitors of P-glycoprotein (P-gp). P-gp inhibitors and the use of suchcompounds are known to those skilled in the art. See for example, CancerResearch, 53, 4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996),Cancer Research, 56, 4171-4179 (1996), International PublicationsWO99/64001 and WO01/10387. The important thing is that the blood levelof the P-gp inhibitor be such that it exerts its effect in inhibitingP-gp from decreasing brain blood levels of the compounds of formula (A).To that end the P-gp inhibitor and the compounds of formula (A) can beadministered at the same time, by the same or different route ofadministration, or at different times. The important thing is not thetime of administration but having an effective blood level of the P-gpinhibitor.

Suitable P-gp inhibitors include cyclosporin A, verapamil, tamoxifen,quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone,rapamycin, 10,11-methanodibenzosuberane, phenothiazines, acridinederivatives such as GF120918, FK506, VX-710, LY335979, PSC-833,GF-102,918 and other steroids. It is to be understood that additionalagents will be found that have the same function and therefore achievethe same outcome; such compounds are also considered to be useful.

The P-gp inhibitors can be administered orally, parenterally, (IV, IM,IM-depo, SQ, SQ-depo), topically, sublingually, rectally, intranasally,intrathecally and by implant.

The therapeutically effective amount of the P-gp inhibitors is fromabout 0.1 to about 300 mg/kg/day, preferably about 0.1 to about 150mg/kg daily. It is understood that while a patient may be started on onedose, that dose may have to be varied over time as the patient'scondition changes.

When administered orally, the P-gp inhibitors can be administered inusual dosage forms for oral administration as is known to those skilledin the art. These dosage forms include the usual solid unit dosage formsof tablets and capsules as well as liquid dosage forms such assolutions, suspensions and elixirs. When the solid dosage forms areused, it is preferred that they be of the sustained release type so thatthe P-gp inhibitors need to be administered only once or twice daily.The oral dosage forms are administered to the patient one thru fourtimes daily. It is preferred that the P-gp inhibitors be administeredeither three or fewer times a day, more preferably once or twice daily.Hence, it is preferred that the P-gp inhibitors be administered in soliddosage form and further it is preferred that the solid dosage form be asustained release form which permits once or twice daily dosing. It ispreferred that what ever dosage form is used, that it be designed so asto protect the P-gp inhibitors from the acidic environment of thestomach. Enteric coated tablets are well known to those skilled in theart. In addition, capsules filled with small spheres each coated toprotect from the acidic stomach, are also well known to those skilled inthe art.

In addition, the P-gp inhibitors can be administered parenterally. Whenadministered parenterally they can be administered IV, IM, depo-IM, SQor depo-SQ.

The P-gp inhibitors can be given sublingually. When given sublingually,the P-gp inhibitors should be given one thru four times daily in thesame amount as for IM administration.

The P-gp inhibitors can be given intranasally. When given by this routeof administration, the appropriate dosage forms are a nasal spray or drypowder as is known to those skilled in the art. The dosage of the P-gpinhibitors for intranasal administration is the same as for IMadministration.

The P-gp inhibitors can be given intrathecally. When given by this routeof administration the appropriate dosage form can be a parenteral dosageform as is known to those skilled in the art.

The P-gp inhibitors can be given topically. When given by this route ofadministration, the appropriate dosage form is a cream, ointment orpatch. Because of the amount of the P-gp inhibitors needed to beadministered the patch is preferred. However, the amount that can bedelivered by a patch is limited. Therefore, two or more patches may berequired. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the P-gpinhibitors be delivered as is known to those skilled in the art.

The P-gp inhibitors can be administered rectally by suppository as isknown to those skilled in the art.

The P-gp inhibitors can be administered by implants as is known to thoseskilled in the art.

There is nothing novel about the route of administration nor the dosageforms for administering the P-gp inhibitors. Given a particular P-gpinhibitor, and a desired dosage form, one skilled in the art would knowhow to prepare the appropriate dosage form for the P-gp inhibitor.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsof the invention administered, the particular condition being treated,the severity of the condition being treated, the age, weight, generalphysical condition of the particular patient, and other medication theindividual may be taking as is well known to administering physicianswho are skilled in this art.

Inhibition of APP Cleavage

The compounds of the invention inhibit cleavage of APP between Met595and Asp596 numbered for the APP695 isoform, or a mutant thereof, or at acorresponding site of a different isoform, such as APP751 or APP770, ora mutant thereof (sometimes referred to as the “beta secretase site”).While not wishing to be bound by a particular theory, inhibition ofbeta-secretase activity is thought to inhibit production of beta amyloidpeptide (A beta). Inhibitory activity is demonstrated in one of avariety of inhibition assays, whereby cleavage of an APP substrate inthe presence of a beta-secretase enzyme is analyzed in the presence ofthe inhibitory compound, under conditions normally sufficient to resultin cleavage at the beta-secretase cleavage site. Reduction of APPcleavage at the beta-secretase cleavage site compared with an untreatedor inactive control is correlated with inhibitory activity. Assaysystems that can be used to demonstrate efficacy of the compoundinhibitors of the invention are known. Representative assay systems aredescribed, for example, in U.S. Pat. Nos. 5,942,400, 5,744,346, as wellas in the Examples below.

The enzymatic activity of beta-secretase and the production of A betacan be analyzed in vitro or in vivo, using natural, mutated, and/orsynthetic APP substrates, natural, mutated, and/or synthetic enzyme, andthe test compound. The analysis may involve primary or secondary cellsexpressing native, mutant, and/or synthetic APP and enzyme, animalmodels expressing native APP and enzyme, or may utilize transgenicanimal models expressing the substrate and enzyme. Detection ofenzymatic activity can be by analysis of one or more of the cleavageproducts, for example, by immunoassay, fluorometric or chromogenicassay, HPLC, or other means of detection. Inhibitory compounds aredetermined as those having the ability to decrease the amount ofbeta-secretase cleavage product produced in comparison to a control,where beta-secretase mediated cleavage in the reaction system isobserved and measured in the absence of inhibitory compounds.

Beta-Secretase

Various forms of beta-secretase enzyme are known, and are available anduseful for assay of enzyme activity and inhibition of enzyme activity.These include native, recombinant, and synthetic forms of the enzyme.Human beta-secretase is known as Beta Site APP Cleaving Enzyme (BACE),Asp2, and memapsin 2, and has been characterized, for example, in U.S.Pat. No. 5,744,346 and published PCT patent applications WO98/22597,WO00/03819, WO01/23533, and WO00/17369, as well as in literaturepublications (Hussain et al., 1999, Mol. Cell. Neurosci. 14:419-427;Vassar et al., 1999, Science 286:735-741; Yan et al., 1999, Nature402:533-537; Sinha et al., 1999, Nature 40:537-540; and Lin et al.,2000, PNAS USA 97:1456-1460). Synthetic forms of the enzyme have alsobeen described (WO98/22597 and WO00/17369). Beta-secretase can beextracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

Preferred compounds are effective to inhibit 50% of beta-secretaseenzymatic activity at a concentration of less than 200 micromolar,preferably, 50 micromolar, preferably at a concentration of 10micromolar or less, more preferably 1 micromolar or less, and mostpreferably 10 nanomolar or less.

APP Substrate

Assays that demonstrate inhibition of beta-secretase-mediated cleavageof APP can utilize any of the known forms of APP, including the 695amino acid “normal” isotype described by Kang et al., 1987, Nature325:733-6, the 770 amino acid isotype described by Kitaguchi et. al.,1981, Nature 331:530-532, and variants such as the Swedish Mutation(KM670-1NL) (APP-SW), the London Mutation (V7176F), and others. See, forexample, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet.1:233-234, for a review of known variant mutations. Additional usefulsubstrates include the dibasic amino acid modification, APP-KKdisclosed, for example, in WO 00/17369, fragments of APP, and syntheticpeptides containing the beta-secretase cleavage site, wild type (WT) ormutated form, e.g., SW, as described, for example, in U.S. Pat. No.5,942,400 and WO00/03819.

The APP substrate contains the beta-secretase cleavage site of APP(KM-DA or NL-DA) for example, a complete APP peptide or variant, an APPfragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful for enzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

Antibodies

Products characteristic of APP cleavage can be measured by immunoassayusing various antibodies, as described, for example, in Pirttila et al.,1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect A beta include, for example, the monoclonalantibody 6E10 (Senetek, St. Louis, Mo.) that specifically recognizes anepitope on amino acids 1-16 of the A beta peptide; antibodies 162 and164 (New York State Institute for Basic Research, Staten Island, N.Y.)that are specific for human A beta 1-40 and 1-42, respectively; andantibodies that recognize the junction region of beta-amyloid peptide,the site between residues 16 and 17, as described in U.S. Pat. No.5,593,846. Antibodies raised against a synthetic peptide of residues 591to 596 of APP and SW192 antibody raised against 590-596 of the Swedishmutation are also useful in immunoassay of APP and its cleavageproducts, as described in U.S. Pat. Nos. 5,604,102 and 5,721,130.

Assay Systems

Assays for determining APP cleavage at the beta-secretase cleavage siteare well known in the art. Exemplary assays, are described, for example,in U.S. Pat. Nos. 5,744,346 and 5,942,400, and described in the Examplesbelow.

Cell Free Assays

Exemplary assays that can be used to demonstrate the inhibitory activityof the compounds of the invention are described, for example, inWO00/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346.Such assays can be performed in cell-free incubations or in cellularincubations using cells expressing a beta-secretase and an APP substratehaving a beta-secretase cleavage site.

An APP substrate containing the beta-secretase cleavage site of APP, forexample, a complete APP or variant, an APP fragment, or a recombinant orsynthetic APP substrate containing the amino acid sequence: KM-DA orNL-DA, is incubated in the presence of beta-secretase enzyme, a fragmentthereof, or a synthetic or recombinant polypeptide variant havingbeta-secretase activity and effective to cleave the beta-secretasecleavage site of APP, under incubation conditions suitable for thecleavage activity of the enzyme. Suitable substrates optionally includederivatives that may be fusion proteins or peptides that contain thesubstrate peptide and a modification useful to facilitate thepurification or detection of the peptide or its beta-secretase cleavageproducts. Useful modifications include the insertion of a knownantigenic epitope for antibody binding; the linking of a label ordetectable moiety, the linking of a binding substrate, and the like.

Suitable incubation conditions for a cell-free in vitro assay include,for example: approximately 200 nanomolar to 10 micromolar substrate,approximately 10 to 200 picomolar enzyme, and approximately 0.1nanomolar to 10 micromolar inhibitor compound, in aqueous solution, atan approximate pH of 4-7, at approximately 37 degrees C., for a timeperiod of approximately 10 minutes to 3 hours. These incubationconditions are exemplary only, and can be varied as required for theparticular assay components and/or desired measurement system.Optimization of the incubation conditions for the particular assaycomponents should account for the specific beta-secretase enzyme usedand its pH optimum, any additional enzymes and/or markers that might beused in the assay, and the like. Such optimization is routine and willnot require undue experimentation.

One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No. 5,942,400.

Cellular Assay

Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A beta. Contact of an APPsubstrate with a beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

In one embodiment, cells that naturally express beta-secretase are used.Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

Human cell lines that normally process A beta from APP provide a usefulmeans to assay inhibitory activities of the compounds of the invention.Production and release of A beta and/or other cleavage products into theculture medium can be measured, for example by immunoassay, such asWestern blot or enzyme-linked immunoassay (EIA) such as by ELISA.

Cells expressing an APP substrate and an active beta-secretase can beincubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as A beta.

Although both neural and non-neural cells process and release A beta,levels of endogenous beta-secretase activity are low and often difficultto detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to A beta, and/orenhanced production of A beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A beta that can be readily measured.

In such assays, for example, the cells expressing APP and beta-secretaseare incubated in a culture medium under conditions suitable forbeta-secretase enzymatic activity at its cleavage site on the APPsubstrate. On exposure of the cells to the compound inhibitor, theamount of A beta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

Preferred cells for analysis of beta-secretase activity include primaryhuman neuronal cells, primary transgenic animal neuronal cells where thetransgene is APP, and other cells such as those of a stable 293 cellline expressing APP, for example, APP-SW.

In Vivo Assays: Animal Models

Various animal models can be used to analyze beta-secretase activityand/or processing of APP to release A beta, as described above. Forexample, transgenic animals expressing APP substrate and beta-secretaseenzyme can be used to demonstrate inhibitory activity of the compoundsof the invention. Certain transgenic animal models have been described,for example, in U.S. Pat. Nos. 5,877,399; 5,612,486; 5,387,742;5,720,936; 5,850,003; 5,877,015, and 5,811,633, and in Ganes et al.,1995, Nature 373:523. Preferred are animals that exhibit characteristicsassociated with the pathophysiology of AD. Administration of thecompound inhibitors of the invention to the transgenic mice describedherein provides an alternative method for demonstrating the inhibitoryactivity of the compounds. Administration of the compounds in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount is alsopreferred.

Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of A beta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forA beta deposits or plaques is preferred.

On contacting an APP substrate with a beta-secretase enzyme in thepresence of an inhibitory compound of the invention and under conditionssufficient to permit enzymatic mediated cleavage of APP and/or releaseof A beta from the substrate, the compounds of the invention areeffective to reduce beta-secretase-mediated cleavage of APP at thebeta-secretase cleavage site and/or effective to reduce released amountsof A beta. Where such contacting is the administration of the inhibitorycompounds of the invention to an animal model, for example, as describedabove, the compounds are effective to reduce A beta deposition in braintissues of the animal, and to reduce the number and/or size of betaamyloid plaques. Where such administration is to a human subject, thecompounds are effective to inhibit or slow the progression of diseasecharacterized by enhanced amounts of A beta, to slow the progression ofAD in the, and/or to prevent onset or development of AD in a patient atrisk for the disease.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs. All patents and publications referredto herein are hereby incorporated by reference for all purposes.

Definitions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The symbol “-” in general represents a bond between two atoms in thechain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃ represents a2-substituted-1-methoxypropane compound. In addition, the symbol “-”represents the point of attachment of the substituent to a compound.Thus for example aryl(C₁-C₆)alkyl-indicates an alkylaryl group, such asbenzyl, attached to the compound at the alkyl moiety.

Where multiple substituents are indicated as being attached to astructure, it is to be understood that the substituents can be the sameor different. Thus for example “R_(m) optionally substituted with 1, 2or 3 R_(q) groups” indicates that R_(m) is substituted with 1, 2, or 3R_(q) groups where the R_(q) groups can be the same or different.

APP, amyloid precursor protein, is defined as any APP polypeptide,including APP variants, mutations, and isoforms, for example, asdisclosed in U.S. Pat. No. 5,766,846.

A beta, amyloid beta peptide, is defined as any peptide resulting frombeta-secretase mediated cleavage of APP, including peptides of 39, 40,41, 42, and 43 amino acids, and extending from the beta-secretasecleavage site to amino acids 39, 40, 41, 42, or 43.

Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl protease thatmediates cleavage of APP at the amino-terminal edge of A beta. Humanbeta-secretase is described, for example, in WO00/17369.

Pharmaceutically acceptable refers to those properties and/or substancesthat are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

A therapeutically effective amount is defined as an amount effective toreduce or lessen at least one symptom of the disease being treated or toreduce or delay onset of one or more clinical markers or symptoms of thedisease.

By “alkyl” and “IC₁-C₆ alkyl” in the invention is meant straight orbranched chain alkyl groups having 1-6 carbon atoms, such as, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. It is understood that in cases where an alkyl chain of asubstituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter orlonger than 6 carbons, it will be so indicated in the second “C” as, forexample, “C₁-C₁₀” indicates a maximum of 10 carbons.

By “alkoxy” and “C₁-C₆ alkoxy” in the invention is meant straight orbranched chain alkyl groups having 1-6 carbon atoms, attached through atleast one divalent oxygen atom, such as, for example, methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.

By the term “halogen” in the invention is meant fluorine, bromine,chlorine, and iodine.

“Alkenyl” and “C₂-C₆ alkenyl” means straight and branched hydrocarbonradicals having from 2 to 6 carbon atoms and from one to three doublebonds and includes, for example, ethenyl, propenyl, 1-but-3-enyl,1-pent-3-enyl, 1-hex-5-enyl and the like.

“Alkynyl” and “C₂-C₆ alkynyl” means straight and branched hydrocarbonradicals having from 2 to 6 carbon atoms and one or two triple bonds andincludes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

As used herein, the term “cycloalkyl” refers to saturated carbocyclicradicals having three to twelve carbon atoms. The cycloalkyl can bemonocyclic, or a polycyclic fused system. Examples of such radicalsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. The cycloalkyl groups herein are unsubstituted or, asspecified, substituted in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano,nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆) alkylamino (C₁-C₆) alkyl.

By “aryl” is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted. Preferred aryl groups of the invention are phenyl,1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl or6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. For example, such aryl groups may beoptionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, —COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)N(mono- or di-C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl),—O—C(═O) (C₁-C₆ alkyl), —NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)-SO₂—(C₁-C₆ alkyl), —NH—C(═O)NH₂, —NH—C(═O)N(mono- or di-C₁-C₆alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or —NH(C₁-C₆ alkyl)-C(═O)—N-(mono- ordi-C₁-C₆ alkyl).

By “heteroaryl” is meant one or more aromatic ring systems of 5-, 6-, or7-membered rings which includes fused ring systems of 9-11 atomscontaining at least one and up to four heteroatoms selected fromnitrogen, oxygen, or sulfur. Preferred heteroaryl groups of theinvention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroarylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, suchheteroaryl groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, —COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)N(mono- or di-C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl),—O—C(═O)(C₁-C₆ alkyl), —NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)-SO₂—(C₁-C₆ alkyl), —NH—C(═O)NH₂, —NH—C(═O)N(mono- or di-C₁-C₆alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or —NH(C₁-C₆ alkyl)-C(═O)—N-(mono- ordi-C₁-C₆ alkyl).

By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meant one ormore carbocyclic ring systems of 3-, 4-, 5-, 6-, or 7-membered ringswhich includes fused ring systems of 9-11 atoms containing at least oneand up to four heteroatoms selected from nitrogen, oxygen, or sulfur.Preferred heterocycles of the invention include morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, azepanyl, diazepanyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.The heterocycle groups herein maybe unsubstituted or, as specified,substituted in one or more substitutable positions with various groups.For example, such heterocycle groups may be optionally substituted withC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl or═O.

All patents and publications referred to herein are hereby incorporatedby reference for all purposes.

Structures were named using Name Pro IUPAC Naming Software, version5.09, available from Advanced Chemical Development, Inc., 90 AdelaideStreet West, Toronto, Ontario, M5H 3V9, Canada.

The invention may be better understood with reference to the followingexamples. These examples are intended to be representative of specificembodiments of the invention, and are not intended as limiting the scopeof the invention.

CHEMISTRY EXAMPLES

The following abbreviations may be used in the Examples:

-   -   EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or the        hydrochloride salt or ester);    -   DIEA (diisopropylethylamine);    -   PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate);    -   HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate);    -   DCM (dichloromethane).

Examples

The following examples are given as non-limiting illustration of theinvention.

Synthesis of Compound (IVa):N-(3,5-Difluorobenzyl)-5-methyl-N′,N′-dipropylisophthalamide from5-methyl-N,N-dipropylisophthalamic acid and 3,5-difluorobenzylamine

5-Methyl-N,N-dipropylisophthalamic acid (1.0 mmol) was dissolved in drydichloromethane (10 mL) and 3,5-difluorobenzylamine (1.0 equiv) wasadded by syringe at 0° C. Triethylamine (3.0 equiv),1-hydroxybenzotriazole hydrate (1.5 equiv) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equiv)were added in succession with stirring at 0° C. The resulting mixturewas stirred at 0° C. for 10 min. then allowed to warm to rt for 2 h. Thereaction mixture was then cooled to 0° C., diluted with 10% citric acid(aq), and extracted with ethyl acetate (3×). The combined organicextracts were washed (saturated NaHCO₃, saturated NaCl), dried (MgSO₄),filtered and concentrated under vacuum. This oil was >95% pure byHPLC/MS analysis: R_(f)=0.27 (40% ethyl acetate/hexanes); MS(ES)=389.2.

Synthesis of Compound (VIa):N-(3,5-Difluorobenzyl)-5-methyl-N-(R)-oxiranylmethyl-N′,N′-dipropylisophthalamidefrom N-(3,5-Difluorobenzyl)-5-methyl-N′,N′-dipropylisophthalamide and(R)-glycidyl toluenesulfonate

N-(3,5-Difluorobenzyl)-5-methyl-N′,N′-dipropylisophthalamide (1.0 equiv)was dissolved in dry DMF (0.06 M in amide) and cooled to 0° C. Sodiumhydride (60% dispersion in mineral oil, 1.3 equiv) was added at 0° C.After stirring at 0° C. for 30 min, (R)-glycidyl toluenesulfonate (1.2equiv) was added. The resulting mixture was allowed to warm to rt for17.5 h, whereupon methanol was added, and the mixture was concentrated.The residue was partitioned between ethyl acetate and water. The organiclayer was washed with water, dried (MgSO₄), filtered, and concentrated.The residue was purified by flash chromatography (ethyl acetate/hexaneselution) to give the title compound: R_(f)=0.13 (40% ethylacetate/hexanes); MH+(ES)=445.2.

Synthesis of Compound (VIIIa):N-(3,5-Difluorobenzyl)-N-[2-hydroxy-3-(3-iodobenzylamino)propyl]-5-methyl-N′,N′-dipropylisophthalamidefromN-(3,5-Difluorobenzyl)-5-methyl-N-(R)-oxiranylmethyl-N′,N′-dipropylisophthalamideand 3-iodobenzylamine

N-(3,5-Difluorobenzyl)-5-methyl-N-(R)-oxiranylmethyl-N′,N′-dipropylisophthalamide(1.0 equiv) was dissolved in isopropanol, and 3-iodobenzylamine (1.5equiv) was added at rt. This mixture was heated to reflux for 3 h,whereupon the mixture was concentrated. The residue was purified byflash chromatography (methanol/dichloromethane elution) and thenreversed phase HPLC: MH+(ES)=678.2.

(sat'd NaHCO₃, H₂O, sat'd NaCl), dried (Na₂SO₄), filtered andconcentrated under reduced pressure to give the crude product 2 whichwas used in the next step without further purification (mass spec (ES)(MNa+): 367.1).

Synthesis of (2): phenyl[2-(3,5-difluorophenyl)ethyl](3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)carbamate

The compound (2) can be prepared as follows:

Synthesis of the Isopthalic Amide (IIa)

These compounds are preferably prepared as set forth as follows. Anester, preferably the monomethyl ester of isophthalic acid or methyl5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture.1,1′-Carbonyldiimidazole is added at 20-25 degrees C. The diisopropylamide is added. After 3-24 hr of stirring at 20 degrees C. to the refluxtemperature of the solvent, the reaction mixture is partitioned betweensaturated aqueous ammonium chloride and a water immiscible organicsolvent such as ethyl acetate. The aqueous layer is separated andextracted twice more with the organic solvent (ethyl acetate). Thesolvent removed and the residue thus obtained is basified to yield theisophthalic amide (IIa) in 80% yield.

The following compounds are prepared essentially according to theprocedures described in the schemes, charts, examples and preparationsset forth herein.

Cmpd Structure and/or Name

No.

-   3-    N-(3,5-difluorobenzyl)-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide-   4    N-[2-(3,5-difluorophenyl)ethyl]-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide-   5-    3-[([2-(3,5-difluorophenyl)ethyl]{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)Sulfonyl]-N,N-dipropylbenzamide-   6    N-(3,5-difluorobenzyl)-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide-   7-    N-[2-(3,5-difluorophenyl)ethyl]-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide-   8-    3-{[[2-(3,5-difluorophenyl)ethyl]((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)amino]sulfonyl}-N,N-dipropylbenzamide-   9-    N-(3,5-difluorobenzyl)-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N′,N′,5-trimethylisophthalamide-   10    N-[2-(3,5-difluorophenyl)ethyl]-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N′,N′,    5-trimethylisophthalamide-   11    3-[([2-(3,5-difluorophenyl)ethyl]{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)Sulfonyl]-N,N-dimethylbenzamide-   12-    N-(3,5-difluorobenzyl)-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-N′,N′N,5-trimethylisophthalamide-   13    N-[2-(3,5-difluorophenyl)ethyl]-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-N′,N′,5-trimethylisophthalamide-   14-    3-{[[2-(3,5-difluorophenyl)ethyl]((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)amino]sulfonyl}-N,N-dimethylbenzamide-   15    N-(3-chloro-5-fluorobenzyl)-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide-   16    N-[2-(3-chloro-5-fluorophenyl)ethyl]-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide-   17    3-[([2-(3-chloro-5-fluorophenyl)ethyl]{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)Sulfonyl]-N,N-dipropylbenzamide-   18-    N-(3-chloro-5-fluorobenzyl)-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide-   19    N-[2-(3-chloro-5-fluorophenyl)ethyl]-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide-   20-    3-{[[2-(3-chloro-5-fluorophenyl)ethyl]((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)amino]sulfonyl}-N,N-dipropylbenzamide-   21-    N-[(2R)-3-(benzylamino)-2-hydroxypropyl]-N-(3,5-difluorobenzyl)-5-methyl-N′,N′-dipropylisophthalamide-   22    N-[(2R)-3-(benzylamino)-2-hydroxypropyl]-N-[2-(3,5-difluorophenyl)ethyl]-5-methyl-N′,N′-dipropylisophthalamide-   23    3-({[(2R)-3-(benzylamino)-2-hydroxypropyl][2-(3,5-difluorophenyl)ethyl]amino}sulfonyl)-N,N-dipropylbenzamide.

BIOLOGY EXAMPLES Example A

Enzyme Inhibition Assay

The compounds of the invention are analyzed for inhibitory activity byuse of the MBP-C125 assay. This assay determines the relative inhibitionof beta-secretase cleavage of a model APP substrate, MBP-C125SW, by thecompounds assayed as compared with an untreated control. A detaileddescription of the assay parameters can be found, for example, in U.S.Pat. No. 5,942,400. Briefly, the substrate is a fusion peptide formed ofmaltose binding protein (MBP) and the carboxy terminal 125 amino acidsof APP-SW, the Swedish mutation. The beta-secretase enzyme is derivedfrom human brain tissue as described in Sinha et al, 1999, Nature40:537-540) or recombinantly produced as the full-length enzyme (aminoacids 1-501), and can be prepared, for example, from 293 cellsexpressing the recombinant cDNA, as described in WO00/47618.

Inhibition of the enzyme is analyzed, for example, by immunoassay of theenzyme's cleavage products. One exemplary ELISA uses an anti-MBP captureantibody that is deposited on precoated and blocked 96-well high bindingplates, followed by incubation with diluted enzyme reaction supernatant,incubation with a specific reporter antibody, for example, biotinylatedanti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

Specific Assay Procedure:

Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaOAc, 0.06% TX100, at pH 4.5.

Warming the plates to 37 degrees C. starts the enzyme reaction. After 90minutes at 37 degrees C., 200 microliters/well cold specimen diluent isadded to stop the reaction and 20 microliters/well was transferred to acorresponding anti-MBP antibody coated ELISA plate for capture,containing 80 microliters/well specimen diluent. This reaction isincubated overnight at 4 degrees C. and the ELISA is developed the nextday after a 2 hour incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

Relative compound inhibition potency is determined by calculating theconcentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, preferred compoundsof the invention exhibit an IC₅₀ of less than 200 micromolar, preferablyless than 50 micromolar.

Example B

Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

A synthetic APP substrate that can be cleaved by beta-secretase andhaving N-terminal biotin and made fluorescent by the covalent attachmentof Oregon green at the Cys residue is used to assay beta-secretaseactivity in the presence or absence of the inhibitory compounds of theinvention. Useful substrates include the following:Biotin-SEVNL-DAEFRC[oregon green]KK [SEQ ID NO: 1]Biotin-SEVKM-DAEFRC[oregon green]KK [SEQ ID NO: 2]Biotin-GLNIKTEEISEISY- [SEQ ID NO: 3] EVEFRC[oregon green]KKBiotin-ADRGLTTRPGSGLTNIKTEEISEVNL- [SEQ ID NO: 4] DAEFRC[oregon green]KKBiotin-FVNQHLCoxGSHLVEALY- [SEQ ID NO: 5] LVCoxGERGFFYTPKAC[oregongreen]KK

The enzyme (0.1 nanomolar) and test compounds (0.001-100 micromolar) areincubated in pre-blocked, low affinity, black plates (384 well) at 37degrees for 30 minutes. The reaction is initiated by addition of 150millimolar substrate to a final volume of 30 microliter per well. Thefinal assay conditions are: 0.001-100 micromolar compound inhibitor; 0.1molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1 nanomolarsoluble beta-secretase; 0.001% Tween 20, and 2% DMSO. The assay mixtureis incubated for 3 hours at 37 degrees C., and the reaction isterminated by the addition of a saturating concentration of immunopurestreptavidin. After incubation with streptavidin at room temperature for15 minutes, fluorescence polarization is measured, for example, using aLJL Acqurest (Ex485 nm/Em530 nm). The activity of the beta-secretaseenzyme is detected by changes in the fluorescence polarization thatoccur when the substrate is cleaved by the enzyme. Incubation in thepresence or absence of compound inhibitor demonstrates specificinhibition of beta-secretase enzymatic cleavage of its synthetic APPsubstrate. In this assay, preferred compounds of the invention exhibitan IC₅₀ of less than 200 micromolar, preferably less than 50 micromolar.

Example C

Beta-Secretase Inhibition: P26-P4′SW Assay

Synthetic substrates containing the beta-secretase cleavage site of APPare used to assay beta-secretase activity, using the methods described,for example, in published PCT application WO00/47618. The P26-P4′SWsubstrate is a peptide of the sequence: [SEQ ID NO: 6](biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF.

The P26-P1 standard has the sequence: [SEQ ID NO: 7](biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL.

Briefly, the biotin-coupled synthetic substrates are incubated at aconcentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

The reaction mixture also includes 20 millimolar sodium acetate, pH 4.5,0.06% Triton X100, and is incubated at 37 degrees C. for about 1 to 3hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

Cleavage products can be assayed by ELISA. Diluted samples and standardsare incubated in assay plates coated with capture antibody, for example,SW192, for about 24 hours at 4 degrees C. After washing in TTBS buffer(150 millimolar sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH7.5), the samples are incubated with streptavidin-AP according to themanufacturer's instructions. After a one hour incubation at roomtemperature, the samples are washed in TTBS and incubated withfluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Example D

Assays Using Synthetic Oligopeptide-Substrates

Synthetic oligopeptides are prepared that incorporate the known cleavagesite of beta-secretase, and optionally detectable tags, such asfluorescent or chromogenic moieties. Examples of such peptides, as wellas their production and detection methods are described in U.S. Pat. No.5,942,400, herein incorporated by reference. Cleavage products can bedetected using high performance liquid chromatography, or fluorescent orchromogenic detection methods appropriate to the peptide to be detected,according to methods well known in the art.

By way of example, one such peptide has the sequence SEVNL-DAEF [SEQ IDNO: 8], and the cleavage site is between residues 5 and 6. Anotherpreferred substrate has the sequence ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[SEQ ID NO: 9], and the cleavage site is between residues 26 and 27.

These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Example E

Inhibition of Beta-Secretase Activity—Cellular Assay

An exemplary assay for the analysis of inhibition of beta-secretaseactivity utilizes the human embryonic kidney cell line HEKp293 (ATCCAccession No. CRL-1573) transfected with APP751 containing the naturallyoccurring double mutation Lys651Met52 to Asn651Leu652 (numbered forAPP751), commonly called the Swedish mutation and shown to overproduce Abeta (Citron et al., 1992, Nature 360:672-674), as described in U.S.Pat. No. 5,604,102.

The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Example F

Inhibition of Beta-Secretase in Animal Models of AD

Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

PDAPP mice, prepared as described in Games et al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

Transgenic animals are administered an amount of the compound inhibitorformulated in a carrier suitable for the chosen mode of administration.Control animals are untreated, treated with vehicle, or treated with aninactive compound. Administration can be acute, i.e., single dose ormultiple doses in one day, or can be chronic, i.e., dosing is repeateddaily for a period of days. Beginning at time 0, brain tissue orcerebral fluid is obtained from selected animals and analyzed for thepresence of APP cleavage peptides, including A beta, for example, byimmunoassay using specific antibodies for A beta detection. At the endof the test period, animals are sacrificed and brain tissue or cerebralfluid is analyzed for the presence of A beta and/or beta-amyloidplaques. The tissue is also analyzed for necrosis.

Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Example G

Inhibition of A Beta Production in Human Patients

Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Example H

Prevention of a Beta Production in Patients at Risk for AD

Patients predisposed or at risk for developing AD are identified eitherby recognition of a familial inheritance pattern, for example, presenceof the Swedish Mutation, and/or by monitoring diagnostic parameters.Patients identified as predisposed or at risk for developing AD areadministered an amount of the compound inhibitor formulated in a carriersuitable for the chosen mode of administration. Administration isrepeated daily for the duration of the test period. Beginning on day 0,cognitive and memory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for Cognitive and memory function, as comparedwith control, non-treated patients.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of the formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein R₂₀ isH, C₁₋₆ alkyl or alkenyl, C₁₋₆ haloalkyl or C₄₋₇ cycloalkyl; R₁ is—(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), or C₁-C₁₀ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from halogen, —OH, ═O,—SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino,—N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or C₂-C₆alkenyl or C₂-C₆ alkynyl, each of which is optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino, or aryl,heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, or—C₁-C₆ alkyl-heterocyclyl, where the ring portions of each areoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or—N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono or dialkylamino,—C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or C₁-C₆alkoxy optionally substituted with 1, 2, or 3 groups which areindependently selected from halogen, or C₃-C₇ cycloalkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- ordialkylamino, or C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, or C₂-C₁₀ alkenylor C₂-C₁₀ alkynyl each of which is optionally substituted with 1, 2, or3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; and theheterocyclyl group is optionally further substituted with oxo; R and R′independently are hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkylaryl or C₁-C₁₀alkylheteroaryl; R_(C) is hydrogen, —(CR₂₄₅R₂₅₀)₀₋₄-aryl,—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl, —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl, —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl, (CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl,—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-aryl, —[C(R₂₅₅) (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂,—CH(aryl)₂, —CH(heteroaryl)₂, —CH(heterocyclyl)₂, —CH(aryl)(heteroaryl),—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)—(CH₂)₀₋₁-aryl,—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl, —CH(-aryl or-heteroaryl)-CO—O(C₁-C₄ alkyl), —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂, (C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,—(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀) or C₁-C₁₀ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from the group consistingof R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆ alkyl), —SH,—NR₂₃₅C═ONR₂₃₅R₂₄₀, —C═ONR₂₃₅R₂₄₀, and —S(═O)₂NR₂₃₅R₂₄₀, or—(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionallysubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl), or cyclopentyl,cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, orheterocyclyl wherein one, two or three carbons of the cyclopentyl,cyclohexyl, or cycloheptyl is optionally replaced with a heteroatomindependently selected from NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein thecyclopentyl, cyclohexyl, or cycloheptyl group can be optionallysubstituted with one or two groups that are independently R₂₀₅, ═O,—CO—NR₂₃₅R₂₄₀, or —SO₂—(C₁-C₄ alkyl), or C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl, each of which is optionally substituted with 1, 2, or 3 R₂₀₅groups, wherein each aryl and heteroaryl is optionally substituted with1, 2, or 3 R₂₀₀, and wherein each heterocyclyl is optionally substitutedwith 1, 2, 3, or 4 R₂₁₀; R₂₀₀ at each occurrence is independentlyselected from —OH, —NO₂, halogen, —CO₂H, C≡N, —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅,—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—CO—(C₃-C₇ cycloalkyl),—(CH₂)₀₋₄—CO-aryl, —(CH₂)₀₋₄—CO-heteroaryl, —(CH₂)₀₋₄—CO-heterocyclyl,—(CH₂)₀₋₄—CO—O—R₂₁₅, —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—SO—(C₁-C₈alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂—(C₃-C₇ cycloalkyl),—(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅, —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—N(R₂₁₅)₂,—(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—N(—H or R₂₁₅)—CO—R₂₂₀,—(CH₂)₀₋₄—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—P(O)—(OR₂₄₀)₂, —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂,—(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—O—(R₂₁₅), —(CH₂)₀₋₄—O—(R₂₁₅)—COOH,—(CH₂)₀₋₄—S—(R₂₁₅), —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with1, 2, 3, or 5-F), C₃-C₇ cycloalkyl, —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, or C₁-C₁₀ alkyl optionally substituted with1, 2, or 3 R₂₀₅ groups, or C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each ofwhich is optionally substituted with 1 or 2 R₂₀₅ groups, wherein thearyl and heteroaryl groups at each occurrence are optionally substitutedwith 1, 2, or 3 groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkylsubstituted with 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀,and wherein the heterocyclyl group at each occurrence is optionallysubstituted with 1, 2, or 3 groups that are independently R₂₁₀; R₂₀₅ ateach occurrence is independently selected from C₁-C₆ alkyl, halogen,—OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl) orN-(C₁-C₆ alkyl) (C₁-C₆ alkyl); R₂₁₀ at each occurrence is independentlyselected from halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅, OH,C≡N, —CO—(C₁-C₄ alkyl), —SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂—(C₁-C₄alkyl), ═O, or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₇cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R₂₀₅groups; R₂₁₅ at each occurrence is independently selected from C₁-C₆alkyl, —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocyclyl), wherein the arylgroup at each occurrence is optionally substituted with 1, 2, or 3groups that are independently R₂₀₅ or R₂₁₀, and wherein the heterocyclyland heteroaryl groups at each occurrence are optionally substituted with1, 2, or 3 R₂₁₀; R₂₂₀ and R₂₂₅ at each occurrence are independentlyselected from —H, —C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),—(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆alkyl chain with one double bond and one triple bond, -aryl,-heteroaryl, and -heterocyclyl, or —C₁-C₁₀ alkyl optionally substitutedwith —OH, —NH₂ or halogen, wherein the aryl, heterocyclyl and heteroarylgroups at each occurrence are optionally substituted with 1, 2, or 3R₂₇₀ groups R₂₃₅ and R₂₄₀ at each occurrence are independently H, orC₁-C₆ alkyl; R₂₄₅ and R₂₅₀ at each occurrence are independently selectedfrom —H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄ alkylheteroaryl, C₁-C₄hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(CH₂)₀₋₄—C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and phenyl; or R₂₄₅ and R₂₅₀are taken together with the carbon to which they are attached to form acarbocycle of 3, 4, 5, 6, or 7 carbon atoms, where one carbon atom isoptionally replaced by a heteroatom selected from —O—, —S—, —SO₂—, and—NR₂₂₀—; R₂₅₅ and R₂₆₀ at each occurrence are independently selectedfrom —H, —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), —(C₁-C₄ alkyl)-aryl, —(C₁-C₄alkyl)-heteroaryl, —(C₁-C₄ alkyl)-heterocyclyl, -aryl, -heteroaryl,-heterocyclyl, —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl,—(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl,—(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocyclyl, or C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, each of which is optionallysubstituted with 1, 2, or 3 R₂₀₅ groups, wherein each aryl or phenyl isoptionally substituted with 1, 2, or 3 groups that are independentlyR₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2, or 3 groups that areindependently R₂₀₅ or R₂₁₀, and wherein each heterocyclyl is optionallysubstituted with 1, 2, 3, or 4 R₂₁₀; R₂₆₅ at each occurrence isindependently —O—, —S— or —N(C₁-C₆ alkyl)-; R₂₇₀ at each occurrence isindependently R₂₀₅, halogen C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, NR₂₃₅R₂₄₀,—OH, —C≡N, —CO—(C₁-C₄ alkyl), —SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂—(C₁-C₄alkyl), ═O, or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, each of which is optionally substituted with1, 2, or 3 R₂₀₅ groups; R_(N) is R′₁₀₀, —C(═O)—NR₁₀₀—R′₁₀₀,—C(═O)O—R′₁₀₀, —SO₂R′₁₀₀, —(CRR′)₁₋₆R′₁₀₀, —C(═O)—(CRR′)₀₋₆R₁₀₀,—C(═O)—(CRR′)₁₋₆—O—R′₁₀₀, —C(═O)—(CRR′)₁₋₆—S—R′₁₀₀,—C(═O)—(CRR′)₁₋₆—C(═O)—R₁₀₀, —C(═O)—(CRR′)₁₋₆—SO₂—R₁₀₀,—C(═O)—(CRR′)₁₋₆—NR₁₀₀—R₁₀₀, or

wherein R₄ is selected from the group consisting of H; NH₂;—NH—(CH₂)_(n6)—R₄₋₁; —NHR₈; —NR₅₀C(O)R₅; C₁-C₄ alkyl-NHC(O)R₅;—(CH₂)₀₋₄R₈; —O—C₁-C₄ alkanoyl; OH; C₆-C₁₀ aryloxy optionallysubstituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkyl, —CO₂H, —C(O)—C₁-C₄ alkoxy, or C₁-C₄ alkoxy; C₁-C₆ alkoxy; arylC₁-C₄ alkoxy; —NR₅OCO₂R₅₁; —C₁-C₄ alkyl-NR₅OCO₂R₅₁; —C≡N; —CF₃;—CF₂—CF₃; —C≡CH; —CH₂—CH═CH₂; —(CH₂)₁₋₄—R₄₋₁; —(CH₂)₁₋₄—NH—R₄₋₁;—O—(CH₂)_(n6)—R₄₋₁; —S—(CH₂)_(n6)—R₄₋₁; —(CH₂)₀₋₄—NHC(O)—(CH₂)₀₋₆—R₅₂;—(CH₂)₀₋₄—R₅₃—(CH₂)₀₋₄—R₅₄; wherein n₆ is 0, 1, 2, or 3; n₇ is 0, 1, 2,or 3; R₄₋₁ is selected from the group consisting of —SO₂—(C₁-C₈ alkyl),—SO—(C₁-C₈ alkyl), —S—(C₁-C₈ alkyl), —S—CO—(C₁-C₆ alkyl),—SO₂—NR₄₋₂R₄₋₃; —CO—C₁-C₂ alkyl; —CO—NR₄₋₃R₄₋₄; R₄₋₂ and R₄₋₃ areindependently H, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; R₄₋₄ is alkyl,arylalkyl, alkanoyl, or arylalkanoyl; R₄₋₆ is —H or C₁-C₆ alkyl; R₅ isselected from the group consisting of C₃-C₇ cycloalkyl; C₁-C₆ alkyloptionally substituted with 1, 2, or 3 groups that are independentlyhalogen, —NR₆R₇, C₁-C₄ alkoxy, C₅-C₆ heterocycloalkyl, C₅-C₆ heteroaryl,C₆-C₁₀ aryl, C₃-C₇ cycloalkyl C₁-C₄ alkyl, —S—C₁-C₄ alkyl, —SO₂—C₁-C₄alkyl, —CO₂H, —CONR₆R₇, —CO₂—C₁-C₄ alkyl, C₆-C₁₀ aryloxy; heteroaryloptionally substituted with 1, 2, or 3 groups that are independentlyC₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, or OH;heterocycloalkyl optionally substituted with 1, 2, or 3 groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or C₂-C₄ alkanoyl;aryl optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkyl; and —NR₆R₇; wherein R₆ and R₇ are independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkanoyl, phenyl,—SO₂—C₁-C₄ alkyl, phenyl C₁-C₄ alkyl; R₈ is selected from the groupconsisting of —SO₂-heteroaryl, —SO₂-aryl, —SO₂-heterocycloalkyl,—SO₂—C₁-C₁₀ alkyl, —C(O)NHR₉, heterocycloalkyl, —S—C₁-C₆ alkyl, —S—C₂-C₄alkanoyl, wherein R₉ is aryl C₁-C₄ alkyl, C₁-C₆ alkyl, or H;  R₅₀ is Hor C₁-C₆ alkyl; R₅₁ is selected from the group consisting of aryl C₁-C₄alkyl; C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups thatare independently halogen, cyano, heteroaryl, —NR₆R₇, —C(O)NR₆R₇, C₃-C₇cycloalkyl, or —C₁-C₄ alkoxy; heterocycloalkyl optionally substitutedwith 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,halogen, C₂-C₄ alkanoyl, aryl C₁-C₄ alkyl, and —SO₂ C₁-C₄ alkyl;alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3groups that are independently OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)(C₁-C₆ alkyl); heteroarylalkyloptionally substituted with 1, 2, or 3 groups that are independentlyC₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆alkyl)(C₁-C₆ alkyl); aryl; heterocycloalkyl; C₃-C₈ cycloalkyl; andcycloalkylalkyl; wherein the aryl; heterocycloalkyl, C₃-C₈ cycloalkyl,and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or5 groups that are independently halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkanoyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, hydroxy,C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, C₁-C₆thioalkoxy C₁-C₆ alkyl, or C₁-C₆ alkoxy C₁-C₆ alkoxy; R₅₂ isheterocycloalkyl, heteroaryl, aryl, cycloalkyl, —S(O)₀₋₂-C₁-C₆ alkyl,CO₂H, —C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl) (alkyl), —CO₂-alkyl,—NHS(O)₀₋₂—C₁-C₆ alkyl, —N (alkyl) S(O)₀₋₂—C₁-C₆ alkyl,—S(O)₀₋₂-heteroaryl, —S(O)₀₋₂-aryl, —NH(arylalkyl),—N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently alkyl,alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, NO₂, CN,alkoxycarbonyl, or aminocarbonyl; R₅₃ is absent, —O—, —C(O)—, —NH—,—N(alkyl)-, —NH—S(O)₀₋₂—, —N(alkyl)-S(O)₀₋₂—, —S(O)₀₋₂—NH—,—S(O)₀₋₂—N(alkyl)-, —NH—C(S)—, or —N(alkyl)-C(S)—; R₅₄ is heteroaryl,aryl, arylalkyl, heterocycloalkyl, CO₂H, —CO₂-alkyl, —C(O)NH(alkyl),—C(O)N(alkyl) (alkyl), —C(O)NH₂, C₁-C₈ alkyl, OH, aryloxy, alkoxy,arylalkoxy, NH₂, NH(alkyl), N(alkyl) (alkyl), or —C₁-C₆ alkyl-CO₂—C₁-C₆alkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5groups that are independently alkyl, alkoxy, CO₂H, —CO₂-alkyl,thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO₂,CN, alkoxycarbonyl, or aminocarbonyl; X′ is selected from the groupconsisting of —C₁-C₆ alkylidenyl optionally optionally substituted with1, 2, or 3 methyl groups; and —NR₄₋₆—; or R₄ and R₄₋₆ combine to form—(CH₂)_(n10)—, wherein n₁₀ is 1, 2, 3, or 4; Z is selected from thegroup consisting of a bond; SO₂; SO; S; and C(O); Y is selected from thegroup consisting of H; C₁-C₄ haloalkyl; C₅-C₆ heterocycloalkyl; C₆-C₁₀aryl; OH; —N(Y₁) (Y₂); C₁-C₁₀ alkyl optionally substituted with 1 thru 3substituents which can be the same or different and are selected fromthe group consisting of halogen, hydroxy, alkoxy, thioalkoxy, andhaloalkoxy; C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3groups independently selected from C₁-C₃ alkyl, and halogen; alkoxy;aryl optionally substituted with halogen, alkyl, alkoxy, CN or NO₂;arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or NO₂;wherein Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyloptionally substituted with 1, 2, or 3 substituents selected from thegroup consisting of halogen, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, and OH;C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄alkyl; or C₃-C₈ cycloalkyl C₁-C₄ alkyl; or Y₁, Y₂ and the nitrogen towhich they are attached form a ring selected from the group consistingof piperazinyl, piperidinyl, morpholinyl, and pyrolidinyl, wherein eachring is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, orhalogen; R₁₀₀ and R′₁₀₀ independently represent aryl, heteroaryl,-aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl,-heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,-heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,-heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl,—CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heterocyclyl or —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of eachare optionally substituted with 1, 2, or 3 groups independently selectedfrom —OR, —NO₂, halogen, —C≡N, —OCF₃, —CF₃, —(CH₂)₀₋₄—O—P(═O)(OR)(OR′),—(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′-(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄ (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₀₀,—(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₀₀, —(CH₂)₀₋₄—CO—R₁₂₀,—(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀,—(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl),—(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇cycloalkyl, (C₂-C₁₀) alkenyl, or (C₂-C₁₀)alkynyl, or R₁₀₀ is C₁-C₁₀alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups, or R₁₀₀ is—(C₁-C₆ alkyl)-O—C₁-C₆ alkyl) or —(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl), each ofwhich is optionally substituted with 1, 2, or 3 R₁₁₅ groups, or R₁₀₀ isC₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups; Wis —(CH₂)₀₋₄—, —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—; R₁₀₂ andR₁₀₂′ independently are hydrogen, or C₁-C₁₀ alkyl optionally substitutedwith 1, 2, or 3 groups that are independently halogen, aryl or —R₁₁₀;R₁₀₅ and R₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl chain with onedouble bond and one triple bond, or C₁-C₆ alkyl optionally substitutedwith —OH or —NH₂; or, C₁-C₆ alkyl optionally substituted with 1, 2, or 3groups independently selected from halogen, or R₁₀₅ and R′₁₀₅ togetherwith the atom to which they are attached form a 3 to 7 memberedcarbocylic ring, where one member is optionally a heteratom selectedfrom —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the ring being optionally substitutedwith 1, 2 or three R₁₄₀ groups; R₁₁₅ at each occurrence is independentlyhalogen, —OH, —CO₂R₁₀₂, —C₁-C₆ thioalkoxy, —CO₂-phenyl, —NR₁₀₅R′₁₃₅,—SO₂—(C₁-C₈ alkyl) —C(═O)R₁₈₀, R₁₈₀, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅,—NH—CO—(C₁-C₆ alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,—O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino,—O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆alkoxy or C₁-C₆ haloalkoxy; R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₇ cycloalkyl, —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or—(CH₂)₀₋₂-(heterocyclyl); R₁₄₀ is heterocyclyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono (C₁-C₆) alkylamino (C₁-C₆)alkyl, di(C₁-C₆) alkylamino (C₁-C₆)alkyl, and ═O; R₁₅₀ is hydrogen,C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one triple bond,—R₁₁₀, —R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4groups independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, andhalogen; R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl),C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and onetriple bond, —R₁₁₀, —R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1,2, 3, or 4 groups independently selected from —OH, —NH₂, C₁-C₃ alkoxy,R₁₁₀, and halogen; R₁₈₀ is selected from morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyland pyrrolidinyl, each of which is optionally substituted with 1, 2, 3,or 4 groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆) alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono (C₁-C₆) alkylamino (C₁-C₆) alkyl,di(C₁-C₆) alkylamino (C₁-C₆)alkyl, and ═O; R₁₁₀ is aryl optionallysubstituted with 1 or 2 R₁₂₅ groups; R₁₂₅ at each occurrence isindependently halogen, amino, mono- or dialkylamino, —OH, —C≡N,—SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl),—CO—NH₂, —CO—NH—C₁-C₆ alkyl, or —CO—N(C₁-C₆ alkyl)₂, or C₁-C₆ alkyl,C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substitutedwith 1, 2, or 3 groups that are independently selected from C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- anddialkylamino, or C₁-C₆ alkoxy optionally substituted with one, two orthree of halogen; R₁₂₀ is heteroaryl, which is optionally substitutedwith 1 or 2 R₁₂₅ groups; and R₁₃₀ is heterocyclyl optionally substitutedwith 1 or 2 R₁₂₅ groups; and R₂ is selected from the group consisting ofH; C₁-C₆ alkyl, optionally substituted with 1, 2, or 3 substituents thatare independently selected from the group consisting of C₁-C₃ alkyl,halogen, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and —NR_(1-a)R_(1-b);wherein R_(1-a) and R_(1-b) are —H or C₁-C₆ alkyl; (CH₂)₀₋₄-aryl;—(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl; C₂-C₆ alkynyl; —CONR_(N-2)R_(N-3);—SO₂NR_(N-2)R_(N-3); —CO₂H; and —CO₂—(C₁-C₄ alkyl); R₃ is selected fromthe group consisting of H; C₁-C₆ alkyl, optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofc₁-C₃ alkyl, halogen, —OH, —SH, —C—N, —CF₃, C₁-C₃ alkoxy, and—NR_(1-a)R_(1-b); —(CH₂)₀₋₄-aryl; —(CH₂)₀₋₄-heteroaryl; C₂-C₆ alkenyl;C₂-C₆ alkynyl; —CO—NR_(n-2)R_(n-3); —SO₂—NR_(n-2)R_(n-3); —CO₂H; and—CO—O—(C₁-C₄ alkyl); wherein R_(N-2) and R_(N-3) at each occurrence areindependently selected from the group consisting of —C₁-C₈ alkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of —OH, —NH₂, phenyl and halogen; —C₃-C₆cycloalkyl; —(C₁-C₂ alkyl)-(C₃-C₈ cycloalkyl); —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl); —C₂-C₆ alkenyl; —C₂-C₆ alkynyl; —C₁-C₆ alkyl chain with onedouble bond and one triple bond; aryl; heteroaryl; heterocycloalkyl; orR_(N-2), R_(N-3) and the nitrogen to which they are attached form a 5,6, or 7 membered heterocycloalkyl or heteroaryl group, wherein saidheterocycloalkyl or heteroaryl group is optionally fused to a benzene,pyridine, or pyrimidine ring, and said groups are unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that at each occurrence areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, halo C₁-C₆ alkyl, haloC₁-C₆ alkoxy, —CN, —NO₂, —NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆alkyl), —OH, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl) (C₁-C₆alkyl), C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ thioalkoxy, and C₁-C₆ thioalkoxyC₁-C₆ alkyl; or wherein, R₂, R₃ and the carbon to which they areattached form a carbocycle of three thru seven carbon atoms, wherein onecarbon atom is optionally replaced by a group selected from —O—, —S—,—SO₂—, or —NR_(N-2)—.
 2. A compound according to claim 1 wherein RN isR_(N) is R′₁₀₀, —C(═O)—NR₁₀₀—R′₁₀₀, —C(═O)O—R′₁₀₀, —SO₂R′₁₀₀,—(CRR′)₁₋₆R′₁₀₀, —C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O)—(CRR′)₁₋₆—O—R′₁₀₀,—C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, —C(═O)—(CRR′)₁₋₆—C(═O)—R₁₀₀,—C(═O)—(CRR′)₁₋₆—SO₂—R₁₀₀, or —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀.
 3. Acompound according to claim 1, wherein R_(N) is

wherein X′ is C₁-C₄ alkylidenyl optionally substituted with 1, 2, or 3methyl groups; or —NR₄₋₆—, where R₄₋₆ is —H or C₁-C₆ alkyl; or R₄ andR₄₋₆ combine to form —(CH₂)_(n10)—, wherein n₁₀ is 1, 2, 3, or 4; Z isselected from a bond; SO₂; SO; S; and C(O); Y is selected from H; C₁-C₄haloalkyl; C₅-C₆ heterocycloalkyl containing at least one N, O, or S;phenyl; OH; —N(Y₁) (Y₂); C₁-C₁₀ alkyl optionally substituted with 1 thru3 substituents which can be the same or different and are selected fromhalogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C₃-C₈ cycloalkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom C₁-C₃ alkyl, and halogen; alkoxy; phenyl optionally substitutedwith halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN or NO₂; phenyl C₁-C₄ alkyloptionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN orNO₂; wherein Y₁ and Y₂ are the same or different and are H; C₁-C₁₀ alkyloptionally substituted with 1, 2, or 3 substituents selected from thegroup consisting of halogen, C₁-C₄ alkoxy, C₃-C₈ cycloalkyl, and OH;C₂-C₆ alkenyl; C₂-C₆ alkanoyl; phenyl; —SO₂—C₁-C₄ alkyl; phenyl C₁-C₄alkyl; and C₃-C₈ cycloalkyl C₁-C₄ alkyl; or —N(Y₁) (Y₂) forms a ringselected from piperazinyl, piperidinyl, morpholinyl, and pyrolidinyl,wherein each ring is optionally substituted with 1, 2, 3, or 4 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆alkyl, or halogen.
 4. A compound according to claim 1, wherein R₁ isaryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring portionsof each are optionally substituted with 1, 2, 3, or 4 groupsindependently selected from halogen, —OH, —SH, —C—N, —NO₂, —NR₁₀₅R′₁₀₅,—CO₂R, —N(R)COR′, or —N(R)SO₂R′ (where R₁₀₅, R′₁₀₅, R and R′ are asdefined above), —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono ordialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄)alkyl, or C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groupswhich are independently selected from halogen, or C₃-C₇ cycloalkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyland mono- or dialkylamino, or C₁-C₁₀ alkyl optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, orC₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substitutedwith 1, 2, or 3 groups independently selected from halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino;and the heterocyclyl group is optionally further substituted with oxo.5. A compound according to claim 4, wherein R₁ is —C₁-C₆ alkyl-aryl,—C₁-C₆ alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ringportions of each are optionally substituted with 1, 2, 3, or 4 groupsindependently selected from halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅,—CO₂R, —N(R)COR′, or —N(R)SO₂R′ (where R₁₀₅, R′₁₀₅, R and R′ are asdefined above), —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono ordialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄)alkyl, or C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groupswhich are independently selected from halogen, or C₃-C₇ cycloalkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyland mono- or dialkylamino, or C₁-C₁₀ alkyl optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, orC₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substitutedwith 1, 2, or 3 groups independently selected from halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino;and the heterocyclyl group is optionally further substituted with oxo.6. A compound according to claim 1 wherein: R_(N) is —C(═O)—R₁₀₀; andR₁₀₀ represents aryl, or heteroaryl, where the ring portions of each areoptionally substituted with 1, 2, or 3 groups independently selectedfrom —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′-(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀) alkynyl.
 7. Acompound according to claim 1 wherein: R_(C) is hydrogen,—(CR₂₄₅R₂₅₀)₀₋₄-aryl, —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl, C₂-C₁₀ alkyl optionally substituted with1, 2, or 3 groups independently selected from the group consisting ofR₂₀₅, R₁₁₀, R₁₂₀, R₁₃₀, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆ alkyl), —SH,and —S(═O)₂NR₂₃₅R₂₄₀, —(CH₂)₀₃—(C₃-C₈) cycloalkyl wherein the cycloalkylis optionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of R₂₀₅, —CO₂H, and —CO₂—(C₁-C₄ alkyl), orC₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionallysubstituted with 1, 2, or 3 independently selected R₂₀₅ groups, whereineach aryl and heteroaryl is optionally substituted with 1, 2, or 3 R₂₀₀,and wherein each heterocyclyl is optionally substituted with 1, 2, 3, or4 independently selected R₂₁₀ groups.
 8. A compound according to claim 1wherein R₂, R₃, and R₂₀ are each hydrogen.
 9. A compound according toclaim 1 selected from the group consisting of:N-(3,5-difluorobenzyl)-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide;N-[2-(3,5-difluorophenyl)ethyl]-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide;3-[([2-(3,5-difluorophenyl)ethyl]{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)Sulfonyl]-N,N-dipropylbenzamide;N-(3,5-difluorobenzyl)-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide;N-[2-(3,5-difluorophenyl)ethyl]-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide;3-{[[2-(3,5-difluorophenyl)ethyl]((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)amino]sulfonyl}-N,N-dipropylbenzamide;N-(3,5-difluorobenzyl)-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N′,N′,5-trimethylisophthalamide;N-[2-(3,5-difluorophenyl)ethyl]-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N′,N′,5-trimethylisophthalamide;3-[([2-(3,5-difluorophenyl)ethyl]{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)Sulfonyl]-N,N-dimethylbenzamide;N-(3,5-difluorobenzyl)-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-N′,N′,5-trimethylisophthalamide;N-[2-(3,5-difluorophenyl)ethyl]-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-N′,N′,5-trimethylisophthalamide;3-{[[2-(3,5-difluorophenyl)ethyl]((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)amino]sulfonyl}-N,N-dimethylbenzamide;N-(3-chloro-5-fluorobenzyl)-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide;N-[2-(3-chloro-5-fluorophenyl)ethyl]-N-{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N′,N′-dipropylisophthalamide;3-[([2-(3-chloro-5-fluorophenyl)ethyl]{(2R)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)Sulfonyl]-N,N-dipropylbenzamide;N-(3-chloro-5-fluorobenzyl)-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide;N-[2-(3-chloro-5-fluorophenyl)ethyl]-N-((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-5-methyl-N′,N′-dipropylisophthalamide;3-{[[2-(3-chloro-5-fluorophenyl)ethyl]((2R)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)amino]sulfonyl}-N,N-dipropylbenzamide;N-[(2R)-3-(benzylamino)-2-hydroxypropyl]-N-(3,5-difluorobenzyl)-5-methyl-N′,N′-dipropylisophthalamide;N-[(2R)-3-(benzylamino)-2-hydroxypropyl]-N-[2-(3,5-difluorophenyl)ethyl]-5-methyl-N′,N′-dipropylisophthalamide;3-({[(2R)-3-(benzylamino)-2-hydroxypropyl][2-(3,5-difluorophenyl)ethyl]amino}sulfonyl)-N,N-dipropylbenzamide;and salts therof.
 10. A pharmaceutical composition comprising a compoundaccording to claim 1, in combination with a physiologically acceptablecarrier or excipient. 11-12. (canceled)
 13. A method for treating apatient who has, or in preventing a patient from getting, a disease orcondition selected from the group consisting of Alzheimer's disease, forhelping prevent or delay the onset of Alzheimer's disease, for treatingpatients with mild cognitive impairment (MCI) and preventing or delayingthe onset of Alzheimer's disease in those who would progress from MCI toAD, for treating Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobar hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, or diffuse Lewy body typeof Alzheimer's disease and who is in need of such treatment, comprisingadministering to such patient a therapeutically effective amount of acompound of claim
 1. 14. A method for the treatment or prevention ofAlzheimer's disease, mild cognitive impairment Down's syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, other degenerative dementias, dementias ofmixed vascular and degenerative origin, dementia associated withParkinson's disease, dementia associated with progressive supranuclearpalsy, dementia associated with cortical basal degeneration, diffuseLewy body type of Alzheimer's disease comprising administration of atherapeutically effective amount of a compound or salt according toclaim 1, to a patient in need thereof.
 15. A method for making acompound of claim 1.